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    Clinical Trial Results:
    Randomized, Multicenter, Phase III, Open-Label Study of Alectinib versus Crizotinib in Treatment-Naive Anaplastic Lymphoma Kinase-Positive Advanced Non−Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2013-004133-33
    Trial protocol
    		 PL   IT   GB   PT   ES   DE   FR   GR  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Feb 2018
    First version publication date
    23 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BO28984
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Acronym: ALEX
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Medical Communications, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    Interim
    Date of interim/final analysis
    09 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Feb 2017
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to evaluate and compare the efficacy of alectinib compared to crizotinib in patients with treatment-naive anaplastic lymphoma kinase (ALK)-positive advanced non−small cell lung cancer (NSCLC), as measured by investigator assessed progression-free survival (PFS).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Aug 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 30 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 1
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Switzerland: 9
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    China: 10
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Costa Rica: 3
    Country: Number of subjects enrolled
    Egypt: 1
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Guatemala: 1
    Country: Number of subjects enrolled
    Hong Kong: 19
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Korea, Republic of: 48
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    New Zealand: 4
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Singapore: 14
    Country: Number of subjects enrolled
    Serbia: 3
    Country: Number of subjects enrolled
    Thailand: 19
    Country: Number of subjects enrolled
    Turkey: 7
    Country: Number of subjects enrolled
    Ukraine: 4
    Country: Number of subjects enrolled
    United States: 24
    Country: Number of subjects enrolled
    Taiwan: 14
    Worldwide total number of subjects
    303
    EEA total number of subjects
    62
    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)
    233
    From 65 to 84 years
    68
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study recruited treatment-naive subjects with Anaplastic Lymphoma Kinase (ALK)-positive advanced Non-Small Cell Lung Cancer (NSCLC) in 29 countries from August 2014 to January 2016.

    Pre-assignment
    Screening details
    		 A total of 303 subjects were randomized at the time of clinical cut-off (CCO) date and included in the intent-to-treat (ITT) population; 152 participants in the alectinib arm and 151 participants in the crizotinib arm.

    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
    		 Experimental: Alectinib
    Arm description
    		 Subjects received alectinib at 600 mg orally BID from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alectinib
    Investigational medicinal product code
    Other name
    Alecensa
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received alectinib at 600 mg orally BID from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Arm title
    		 Comparator: Crizotinib
    Arm description
    		 Subjects received crizotinib at 250 mg orally BID from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Crizotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received crizotinib at 250 mg orally BID from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Number of subjects in period 1
    		Experimental: Alectinib Comparator: Crizotinib
    Started
    152
    151
    Completed
    0
    0
    Not completed
    152
    151
         Consent withdrawn by subject
    13
    22
         Physician decision
    1
    3
         Adverse event, non-fatal
    -
    2
         Death
    35
    40
         Ongoing at CCOD
    99
    82
         Reason not specified
    1
    -
         Lost to follow-up
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental: Alectinib
    Reporting group description
    		 Subjects received alectinib at 600 mg orally BID from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Reporting group title
    Comparator: Crizotinib
    Reporting group description
    		 Subjects received crizotinib at 250 mg orally BID from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Reporting group values
    		 Experimental: Alectinib Comparator: Crizotinib Total
    Number of subjects
    		 152 151 303
    Age categorical
    Units: Subjects
        <65
    		 115 118 233
        >=65
    		 37 33 70
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.3 ( 12.0 ) 53.8 ( 13.5 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 84 87 171
        Male
    		 68 64 132
    Race/Ethnicity, Customized
    Units: Subjects
        Ethnicity - Hispanic or Latino|
    		 8 8 16
        Ethinicity - Not Hispanic or Latino|
    		 138 136 274
        Ethnicity - Not Stated|
    		 6 7 13
    Race/Ethnicity, Customized
    Units: Subjects
        Race - American Indian or Alaska Native|
    		 4 0 4
        Race - Asian|
    		 69 69 138
        Race - Black or African American|
    		 0 4 4
        Race - Native Hawaiian or other Pacific Islander|
    		 1 1 2
        Race - White|
    		 76 75 151
        Race - Unknown|
    		 2 2 4

    End points

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    End points reporting groups
    Reporting group title
    Experimental: Alectinib
    Reporting group description
    		 Subjects received alectinib at 600 mg orally BID from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Reporting group title
    Comparator: Crizotinib
    Reporting group description
    		 Subjects received crizotinib at 250 mg orally BID from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Primary: Progression-Free Survival (PFS) by Investigator Assessment

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    End point title
    		 Progression-Free Survival (PFS) by Investigator Assessment
    End point description
    PFS was assessed as time to disease progression or death whichever occurred first by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeter (mm) and the appearance of new lesions. 99999 = The value is not available because it had not been reached at the time of data cutoff date (9 Feb 2017).
    End point type
    Primary
    End point timeframe
    Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: months
        median (confidence interval 95%)
    99999 (17.7 to 99999)
    11.1 (9.1 to 13.1)
    Statistical analysis title
    		 PFS by Investigator
    Statistical analysis description
    Stratified hazard ratio and p-value are stratified for covariates Race (Asian vs Non-Asian) and CNS metastases at baseline by Investigator.
    Comparison groups
    Experimental: Alectinib v Comparator: Crizotinib
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard Ratio, stratified
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 0.65

    Primary: Percentage of Participants with PFS event by Investigator assessment

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    End point title
    		 Percentage of Participants with PFS event by Investigator assessment [1]
    End point description
    PFS was assessed percentage of participants with disease progression or death whichever occurred first by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeter (mm) and the appearance of new lesions.
    End point type
    Primary
    End point timeframe
    Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported.
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Percentage of Participants
        number (not applicable)
    40.8
    67.5
    No statistical analyses for this end point

    Secondary: PFS Independent Review Committee (IRC)-assessed

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    End point title
    		 PFS Independent Review Committee (IRC)-assessed
    End point description
    PFS was assessed as time to disease progression or death whichever occurred first by IRC assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm and the appearance of new lesions. 99999 = The value is not available because it had not been reached at the time of data cutoff date (9 Feb 2017).
    End point type
    Secondary
    End point timeframe
    Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: months
        median (confidence interval 95%)
    25.7 (19.9 to 99999)
    10.4 (7.7 to 14.6)
    Statistical analysis title
    		 PFS by IRC
    Statistical analysis description
    Stratified hazard ratio and p-value are stratified for covariates Race (Asian vs Non-Asian) and CNS metastases at baseline by IRC.
    Comparison groups
    Experimental: Alectinib v Comparator: Crizotinib
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.7

    Secondary: Percentage of Participants with Central Nervous System (CNS) Progression as Determined by IRC Using RECIST V1.1 Criteria.

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    End point title
    		 Percentage of Participants with Central Nervous System (CNS) Progression as Determined by IRC Using RECIST V1.1 Criteria.
    End point description
    Time to CNS progression was assessed as percentage of participants with event defined as time from randomization until first radiographic evidence of CNS progression by IRC. The risk for a CNS progression without a prior non-CNS progression with alectinib compared with crizotinib.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression in the CNS (assessed every 8 weeks up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Percentage of Participants
        number (not applicable)
    11.8
    45.0
    Statistical analysis title
    		 CNS progression by IRC using RECIST v1.1
    Comparison groups
    Experimental: Alectinib v Comparator: Crizotinib
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Cause-Specific Hazard Ratio
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.28
    Notes
    [2] - IRC, RECIST v1.1 Stratified Analysis (by race (Asian vs non-Asian) and CNS metastases at baseline by IRC)

    Secondary: Percentage of Participants With Objective Response Rate (ORR) of Complete Response (CR) or Partial Response (PR) as Determined by The Investigators According to RECIST V1.1 Criteria

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    End point title
    		 Percentage of Participants With Objective Response Rate (ORR) of Complete Response (CR) or Partial Response (PR) as Determined by The Investigators According to RECIST V1.1 Criteria
    End point description
    ORR was defined as the percentage of participants who attained CR or PR. As per RECIST v1.1, CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm, PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Percentage of Participants
        number (confidence interval 95%)
    82.9 (75.95 to 88.51)
    75.5 (67.84 to 82.12)
    Statistical analysis title
    		 ORR by Investigator using RECIST v1.1
    Statistical analysis description
    Stratified analysis
    Comparison groups
    Experimental: Alectinib v Comparator: Crizotinib
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0936
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Difference in Overall Response Rates
    Point estimate
    7.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.71
         upper limit
    		 16.5

    Secondary: Duration of Response (DOR) According to RECIST V1.1 Criteria as assessed by the Investigators

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    End point title
    		 Duration of Response (DOR) According to RECIST V1.1 Criteria as assessed by the Investigators
    End point description
    DOR was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death, whichever occurred first. DOR was evaluated for participants who had a best overall response (BOR) of CR or PR. 99999 = The value is not available because it had not been reached at the time of data cutoff date (9 Feb 2017).
    End point type
    Secondary
    End point timeframe
    First occurrence of objective response to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    126
    114
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    11.1 (7.9 to 13.0)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival (OS) was defined as the time from randomization to death from any cause. 99999 = The value is not available because it had not been reached at the time of data cutoff date (9 Feb 2017).
    End point type
    Secondary
    End point timeframe
    From randomization until death (up to 43 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Stratified analysis
    Comparison groups
    Experimental: Alectinib v Comparator: Crizotinib
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2405
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.2

    Secondary: Percentage of Participants with CNS ORR of CR or PR IRC-assessed According to RECIST v1.1 criteria

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    End point title
    		 Percentage of Participants with CNS ORR of CR or PR IRC-assessed According to RECIST v1.1 criteria
    End point description
    CNS ORR was defined as the percentage of participants who attained CR or PR and had measurable CNS lesions at baseline. As per RECIST v1.1, CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm, PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Percentage of Participants
    number (confidence interval 95%)
        Measurable CNS lesions at baseline N=21,22
    81.0 (58.09 to 94.55)
    50.0 (28.22 to 71.78)
        Measurable and non-measurable CNS lesions N=64,58
    59.4 (46.37 to 71.49)
    25.9 (15.26 to 39.04)
    No statistical analyses for this end point

    Secondary: CNS DOR IRC-assessed according to RECIST v1.1 criteria

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    End point title
    		 CNS DOR IRC-assessed according to RECIST v1.1 criteria
    End point description
    CNS DOR was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death, whichever occurred first. DOR was evaluated for participants who had a best overall response (BOR) of CR or PR. 99999 = The value is not available because it had not been reached at the time of data cutoff date (9 Feb 2017).
    End point type
    Secondary
    End point timeframe
    First occurrence of CNS objective response to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    21
    22
    Units: months
        median (confidence interval 95%)
    17.3 (14.8 to 99999)
    5.5 (2.1 to 17.3)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Events

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    End point title
    		 Percentage of Participants With Adverse Events
    End point description
    An adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
    End point type
    Secondary
    End point timeframe
    Baseline up to 28 months in the crizotinib arm and up to 30 months in the alectinib arm
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Percentage of Participants
        number (not applicable)
    97.0
    97.0
    No statistical analyses for this end point

    Secondary: Area Under The Concentration-Time Curve (AUC) of Alectinib

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    End point title
    		 Area Under The Concentration-Time Curve (AUC) of Alectinib [3]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 2 hours before alectinib) (baseline), 1, 2, 4, 6, and 8 hours post-dose at Visit 0 (first dosing day) and Week 4; Pre-dose (within 2 hours) at Week 8, then every 8 weeks until disease progression or death/withdrawal (up to 33 months)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were collected and analyzed for the reported arm only.
    End point values
    		 Experimental: Alectinib
    Number of subjects analysed
    144
    Units: hr*ng/mL
    geometric mean (geometric coefficient of variation)
        Baseline (n=10)
    713 ( 104.9 )
        Treatment - week 4 (n=9)
    5030 ( 47.2 )
    No statistical analyses for this end point

    Secondary: Maximum Concentration (Cmax) of Alectinib

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    End point title
    		 Maximum Concentration (Cmax) of Alectinib [4]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were collected and analyzed for the reported arm only.
    End point values
    		 Experimental: Alectinib
    Number of subjects analysed
    144
    Units: nanogram/milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Baseline (n=10)
    211 ( 55.5 )
        Treatment - week 4 (n=9)
    717 ( 46.8 )
    No statistical analyses for this end point

    Secondary: Time to Reach Cmax (tmax) of Alectinib

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    End point title
    		 Time to Reach Cmax (tmax) of Alectinib [5]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were collected and analyzed for the reported arm only.
    End point values
    		 Experimental: Alectinib
    Number of subjects analysed
    144
    Units: hours
    median (full range (min-max))
        Baseline (n=10)
    6.03 (1.98 to 12.00)
        Treatment - week 4 (n=9)
    4.02 (2.00 to 8.00)
    No statistical analyses for this end point

    Secondary: AUC of Alectinib Metabolite

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    End point title
    		 AUC of Alectinib Metabolite [6]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 2 hours before alectinib) (baseline), 1, 2, 4, 6, and 8 hours post-dose at Visit 0 (first dosing day) and Week 4; Pre-dose (within 2 hours) at Week 8, then every 8 weeks until disease progression or death/withdrawal (up to 33 months)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were collected and analyzed for the reported arm only.
    End point values
    		 Experimental: Alectinib
    Number of subjects analysed
    144
    Units: hr*ng/mL
    geometric mean (geometric coefficient of variation)
        Baseline (n=10)
    142 ( 191.7 )
        Treatment - week 4 (n=9)
    2230 ( 37.0 )
    No statistical analyses for this end point

    Secondary: Cmax of Alectinib Metabolite

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    End point title
    		 Cmax of Alectinib Metabolite [7]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were collected and analyzed for the reported arm only.
    End point values
    		 Experimental: Alectinib
    Number of subjects analysed
    144
    Units: nanogram/milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Baseline (n=10)
    56.2 ( 80.1 )
        Treatment - week 4 (n=9)
    321 ( 32.0 )
    No statistical analyses for this end point

    Secondary: tmax of Alectinib Metabolite

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    End point title
    		 tmax of Alectinib Metabolite [8]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were collected and analyzed for the reported arm only.
    End point values
    		 Experimental: Alectinib
    Number of subjects analysed
    144
    Units: hours
    median (full range (min-max))
        Baseline (n=10)
    8.00 (5.98 to 12.00)
        Treatment - week 4 (n=9)
    6.00 (2.00 to 10.00)
    No statistical analyses for this end point

    Secondary: Time to Deterioration by European Organization for The Research And Treatment of Cancer (EORTC) Quality Of Life Questionnaire Core 30 (C30)

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    End point title
    		 Time to Deterioration by European Organization for The Research And Treatment of Cancer (EORTC) Quality Of Life Questionnaire Core 30 (C30)
    End point description
    The EORTC QLQ-30 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. 99999=not reached at CCOD
    End point type
    Secondary
    End point timeframe
    Baseline, every 4 weeks until disease progression (up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: months
    median (confidence interval 95%)
        Fatigue
    99999 (99999 to 99999)
    99999 (9.4 to 99999)
        Dyspnea
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Fatigue
    Comparison groups
    Experimental: Alectinib v Comparator: Crizotinib
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2079
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.19
    Statistical analysis title
    		 Dyspnea
    Comparison groups
    Experimental: Alectinib v Comparator: Crizotinib
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1137
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 3.15

    Secondary: Time to Deterioration by EORTC Quality of Life Questionnaire Lung Cancer Module 13 (LC13)

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    End point title
    		 Time to Deterioration by EORTC Quality of Life Questionnaire Lung Cancer Module 13 (LC13)
    End point description
    The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
    End point type
    Secondary
    End point timeframe
    Baseline, every 4 weeks until disease progression (up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: months
    median (confidence interval 95%)
        Coughing
    99999 (24.0 to 99999)
    99999 (-99999 to 99999)
        Dyspnoea
    22.8 (11.8 to 99999)
    99999 (21.0 to 99999)
        Pain in arm and shoulder
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
        Pain in chest
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
        Composite score (c, p in c, d)
    12.7 (5.0 to 99999)
    21.0 (9.8 to 99999)
    Statistical analysis title
    		 Coughing
    Comparison groups
    Experimental: Alectinib v Comparator: Crizotinib
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7042
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.74
    Statistical analysis title
    		 Dyspnea
    Comparison groups
    Experimental: Alectinib v Comparator: Crizotinib
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0285
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 2.92
    Statistical analysis title
    		 Pain in arm and shoulder
    Comparison groups
    Experimental: Alectinib v Comparator: Crizotinib
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2377
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 2.61
    Statistical analysis title
    		 Pain in chest
    Comparison groups
    Experimental: Alectinib v Comparator: Crizotinib
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0796
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 1.1
    Statistical analysis title
    		 Cmposite score
    Comparison groups
    Experimental: Alectinib v Comparator: Crizotinib
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6435
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.68

    Secondary: Health-Related Quality of Life (HRQoL) by EORTC Quality of Life Questionnaire C30 Score Global Health Status

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    End point title
    		 Health-Related Quality of Life (HRQoL) by EORTC Quality of Life Questionnaire C30 Score Global Health Status
    End point description
    The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
    End point type
    Secondary
    End point timeframe
    Baseline, every 4 weeks until disease progression (up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Score on a scale
    median (full range (min-max))
        Baseline (n=100, 97)
    66.67 (8.3 to 100.0)
    66.67 (0.0 to 100.0)
        Treatment - week 4 (n=95, 89)
    66.67 (0.0 to 100.0)
    66.67 (16.7 to 100.0)
        Treatment - week 8 (n=89, 84)
    75.0 (16.7 to 100.0)
    75.0 (16.7 to 100.0)
        Treatment - week 12 (n=75, 78)
    75.0 (25.0 to 100.0)
    75.0 (33.3 to 100.0)
        Treatment - week 16 (n=79, 73)
    75.0 (16.7 to 100.0)
    83.33 (16.7 to 100.0)
        Treatment - week 20 (n=73, 67)
    75.0 (16.7 to 100.0)
    75.0 (16.7 to 100.0)
        Treatment - week 24 (n=77, 71)
    75.0 (16.7 to 100.0)
    83.33 (8.3 to 100.0)
        Treatment - week 28 (n=67, 62)
    75.0 (33.3 to 100.0)
    75.0 (33.3 to 100.0)
        Treatment - week 32 (n=73, 65)
    75.0 (33.3 to 100.0)
    66.67 (8.3 to 100.0)
        Treatment - week 36 (n=64, 61)
    79.17 (16.7 to 100.0)
    66.67 (16.7 to 100.0)
        Treatment - week 40 (n=74, 50)
    75.0 (16.7 to 100.0)
    83.33 (33.3 to 100.0)
        Treatment - week 44 (n=62, 47)
    83.33 (16.7 to 100.0)
    83.33 (16.7 to 100.0)
        Treatment - week 48 (n=67, 47)
    66.67 (25.0 to 100.0)
    83.33 (41.7 to 100.0)
        Treatment - week 52 (n=58, 44)
    83.33 (16.7 to 100.0)
    75.00 (41.7 to 100.0)
        Treatment - week 56 (n=61, 48)
    75.0 (16.7 to 100.0)
    75.0 (41.7 to 100.0)
        Treatment - week 60 (n=47, 39)
    75.0 (33.3 to 100.0)
    75.0 (50.0 to 100.0)
        Treatment - week 64 (n=55, 39)
    75.0 (33.3 to 100.0)
    83.33 (41.7 to 100.0)
        Treatment - week 68 (n=49, 34)
    75.0 (33.3 to 100.0)
    79.17 (33.3 to 100.0)
        Treatment - week 72 (n=54, 34)
    75.0 (33.3 to 100.0)
    75.00 (8.3 to 100.0)
        Treatment - week 76 (n=42, 29)
    75.0 (41.7 to 100.0)
    75.0 (16.7 to 100.0)
        Treatment - week 80 (n=43, 23)
    75.0 (33.3 to 100.0)
    75.0 (33.3 to 100.0)
        Treatment - week 84 (n=33, 19)
    83.33 (41.7 to 100.0)
    66.67 (33.3 to 100.0)
        Treatment - week 88 (n=36, 16)
    75.0 (33.3 to 100.0)
    66.67 (33.3 to 100.0)
        Treatment - week 92 (n=30, 13)
    70.83 (33.3 to 100.0)
    75.0 (50.0 to 100.0)
        Treatment - week 96 (n=22, 11)
    66.67 (33.3 to 100.0)
    66.67 (33.3 to 100.0)
        Treatment - week 100 (n=18, 10)
    66.67 (25.0 to 100.0)
    75.0 (33.3 to 100.0)
        Treatment - week 104 (n=15, 7)
    66.67 (50.0 to 100.0)
    66.67 (50.0 to 100.0)
        Treatment - week 108 (n=11, 7)
    66.67 (50.0 to 100.0)
    75.0 (33.3 to 100.0)
        Treatment - week 112 (n=9, 4)
    75.0 (50.0 to 100.0)
    75.0 (33.3 to 100.0)
        Treatment - week 116 (n=4, 2)
    70.83 (41.7 to 100.0)
    91.67 (83.3 to 100.0)
        Treatment - week 120 (n=3, 0)
    83.3 (50.0 to 100.0)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Coughing

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    End point title
    		 HRQoL by EORTC Quality of Life Questionnaire LC13 Score Coughing
    End point description
    The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
    End point type
    Secondary
    End point timeframe
    Baseline, every 4 weeks until disease progression (up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Score on a scale
    median (full range (min-max))
        Baseline (n=100, 96)
    33.33 (0.0 to 100.0)
    33.33 (0.0 to 100.0)
        Treatment - week 4 (n=95, 89)
    33.33 (0.0 to 100.0)
    33.33 (0.0 to 100.0)
        Treatment - week 8 (n=89, 84)
    33.33 (0.0 to 66.7)
    33.33 (0.0 to 100.0)
        Treatment - week 12 (n=75, 78)
    33.33 (0.0 to 100.0)
    0.0 (0.0 to 66.7)
        Treatment - week 16 (n=79, 73)
    0.0 (0.0 to 100.0)
    0.0 (0.0 to 66.7)
        Treatment - week 20 (n=73, 67)
    33.33 (0.0 to 100.0)
    0.0 (0.0 to 66.7)
        Treatment - week 24 (n=77, 71)
    33.33 (0.0 to 100.0)
    33.33 (0.0 to 100.0)
        Treatment - week 28 (n=67, 62)
    33.33 (0.0 to 100.0)
    16.67 (0.0 to 100.0)
        Treatment - week 32 (n=73, 65)
    33.33 (0.0 to 100.0)
    33.33 (0.0 to 100.0)
        Treatment - week 36 (n=64, 61)
    0.0 (0.0 to 100.0)
    0.0 (0.0 to 66.7)
        Treatment - week 40 (n=74, 50)
    33.33 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - week 44 (n=62, 47)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - week 48 (n=67, 47)
    33.33 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - week 52 (n=58, 44)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - week 56 (n=61, 48)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 100.0)
        Treatment - week 60 (n=47, 39)
    33.33 (0.0 to 100.0)
    0.0 (0.0 to 66.7)
        Treatment - week 64 (n=55, 39)
    33.33 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - week 68 (n=49, 34)
    33.33 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - week 72 (n=54, 34)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - week 76 (n=42, 29)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - week 80 (n=43, 23)
    33.33 (0.0 to 66.7)
    0.0 (0.0 to 33.33)
        Treatment - week 84 (n=33, 19)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 33.33)
        Treatment - week 88 (n=36, 16)
    33.33 (0.0 to 100.0)
    0.0 (0.0 to 33.33)
        Treatment - week 92 (n=30, 13)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - week 96 (n=22, 11)
    16.67 (0.0 to 66.7)
    0.0 (0.0 to 33.33)
        Treatment - week 100 (n=18, 10)
    0.0 (0.0 to 100.0)
    0.0 (0.0 to 33.3)
        Treatment - week 104 (n=15, 7)
    33.33 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - week 108 (n=11, 7)
    33.33 (0.0 to 66.7)
    33.33 (0.0 to 33.33)
        Treatment - week 112 (n=9, 4)
    33.33 (0.0 to 33.33)
    0.0 (0.0 to 33.33)
        Treatment - week 116 (n=4, 2)
    33.33 (0.0 to 33.33)
    16.67 (0.0 to 33.33)
        Treatment - week 120 (n=3, 0)
    33.33 (33.33 to 33.33)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Dyspnoea

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    End point title
    		 HRQoL by EORTC Quality of Life Questionnaire LC13 Score Dyspnoea
    End point description
    The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
    End point type
    Secondary
    End point timeframe
    Baseline, every 4 weeks until disease progression (up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Score on a scale
    median (full range (min-max))
        Baseline (n=100, 96)
    22.22 (0.0 to 100.0)
    22.22 (0.0 to 100.0)
        Treatment - Week 4 (n=95, 89)
    22.22 (0.0 to 100.0)
    22.22 (0.0 to 88.9)
        Treatment - Week 8 (n=89, 84)
    22.22 (0.0 to 66.7)
    11.11 (0.0 to 66.7)
        Treatment - Week 12 (n=75, 78)
    22.22 (0.0 to 66.7)
    11.11 (0.0 to 66.7)
        Treatment - Week 16 (n=79, 73)
    22.22 (0.0 to 77.8)
    11.11 (0.0 to 88.9)
        Treatment - Week 20 (n=73, 67)
    22.22 (0.0 to 88.9)
    11.11 (0.0 to 66.7)
        Treatment - Week 24 (n=77, 71)
    22.22 (0.0 to 77.8)
    11.11 (0.0 to 77.8)
        Treatment - Week 28 (n=67, 62)
    11.11 (0.0 to 44.4)
    11.11 (0.0 to 100.0)
        Treatment - Week 32 (n=73, 65)
    22.22 (0.0 to 66.7)
    11.11 (0.0 to 88.9)
        Treatment - Week 36 (n=64, 61)
    16.67 (0.0 to 77.8)
    11.11 (0.0 to 66.7)
        Treatment - Week 40 (n=74, 50)
    11.11 (0.0 to 55.6)
    5.56 (0.0 to 66.7)
        Treatment - Week 44 (n=62, 47)
    11.11 (0.0 to 88.9)
    11.11 (0.0 to 77.8)
        Treatment - Week 48 (n=67, 47)
    22.22 (0.0 to 55.6)
    11.11 (0.0 to 44.4)
        Treatment - Week 52 (n=58, 44)
    22.22 (0.0 to 44.4)
    11.11 (0.0 to 66.7)
        Treatment - Week 56 (n=61, 48)
    22.22 (0.0 to 77.8)
    11.11 (0.0 to 77.8)
        Treatment - Week 60 (n=47, 39)
    22.22 (0.0 to 77.8)
    0.0 (0.0 to 55.6)
        Treatment - Week 64 (n=55, 39)
    22.22 (0.0 to 66.7)
    11.11 (0.0 to 66.7)
        Treatment - Week 68 (n=49, 34)
    22.22 (0.0 to 77.8)
    11.11 (0.0 to 55.6)
        Treatment - Week 72 (n=54, 34)
    22.22 (0.0 to 66.7)
    11.11 (0.0 to 44.4)
        Treatment - Week 76 (n=42, 29)
    11.11 (0.0 to 66.7)
    11.11 (0.0 to 55.6)
        Treatment - Week 80 (n=43, 23)
    22.22 (0.0 to 66.7)
    11.11 (0.0 to 55.6)
        Treatment - Week 84 (n=33, 19)
    11.11 (0.0 to 66.7)
    11.11 (0.0 to 44.4)
        Treatment - Week 88 (n=36, 16)
    22.22 (0.0 to 55.6)
    22.22 (0.0 to 33.3)
        Treatment - Week 92 (n=30, 13)
    22.22 (0.0 to 44.4)
    22.22 (0.0 to 77.8)
        Treatment - Week 96 (n=22, 11)
    22.22 (0.0 to 66.7)
    22.22 (0.0 to 44.4)
        Treatment - Week 100 (n=18, 10)
    22.22 (0.0 to 55.6)
    27.78 (0.0 to 44.4)
        Treatment - Week 104 (n=15, 7)
    11.11 (0.0 to 66.7)
    11.11 (0.0 to 33.3)
        Treatment - Week 108 (n=11, 7)
    22.22 (0.0 to 66.7)
    11.11 (0.0 to 33.3)
        Treatment - Week 112 (n=9, 4)
    11.11 (11.11 to 44.4)
    27.78 (0.0 to 33.3)
        Treatment - Week 116 (n=4, 2)
    16.67 (11.1 to 22.2)
    16.67 (0.0 to 33.3)
        Treatment - Week 120 (n=3, 0)
    22.22 (11.1 to 33.3)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Pain in Chest

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    End point title
    		 HRQoL by EORTC Quality of Life Questionnaire LC13 Score Pain in Chest
    End point description
    The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
    End point type
    Secondary
    End point timeframe
    Baseline, every 4 weeks until disease progression (up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Score on a scale
    median (full range (min-max))
        Baseline (n=100, 96)
    33.33 (0.0 to 100.0)
    0.0 (0.0 to 100.0)
        Treatment - Week 4 (n=95, 89)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 8 (n=89, 84)
    0.0 (0.0 to 33.3)
    0.0 (0.0 to 66.7)
        Treatment - Week 12 (n=75, 78)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 16 (n=79, 73)
    0.0 (0.0 to 33.3)
    0.0 (0.0 to 66.7)
        Treatment - Week 20 (n=73, 67)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 24 (n=77, 71)
    0.0 (0.0 to 33.3)
    0.0 (0.0 to 66.7)
        Treatment - Week 28 (n=67, 62)
    0.0 (0.0 to 33.3)
    0.0 (0.0 to 33.3)
        Treatment - Week 32 (n=73, 65)
    0.00 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 36 (n=64, 61)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 40 (n=74, 50)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 44 (n=62, 47)
    0.0 (0.0 to 100.0)
    0.0 (0.0 to 66.7)
        Treatment - Week 48 (n=67, 47)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 52 (n=58, 44)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 56 (n=61, 48)
    0.0 (0.0 to 33.3)
    0.0 (0.0 to 33.3)
        Treatment - Week 60 (n=47, 39)
    0.0 (0.0 to 33.3)
    0.0 (0.0 to 66.7)
        Treatment - Week 64 (n=55, 39)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 68 (n=49, 34)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 72 (n=54, 34)
    0.0 (0.0 to 33.3)
    0.0 (0.0 to 33.3)
        Treatment - Week 76 (n=42, 29)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 80 (n=43, 23)
    0.0 (0.0 to 33.3)
    0.0 (0.0 to 33.3)
        Treatment - Week 84 (n=33, 19)
    0.0 (0.0 to 33.3)
    0.0 (0.0 to 33.3)
        Treatment - Week 88 (n=36, 16)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 92 (n=30, 13)
    0.0 (0.0 to 33.3)
    0.0 (0.0 to 33.3)
        Treatment - Week 96 (n=22, 11)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 100 (n=18, 10)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 104 (n=15, 7)
    33.33 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 108 (n=11, 7)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 112 (n=9, 4)
    0.0 (0.0 to 66.7)
    16.67 (0.0 to 33.3)
        Treatment - Week 116 (n=4, 2)
    0.0 (0.0 to 33.3)
    16.67 (0.0 to 33.3)
        Treatment - Week 120 (n=3, 0)
    0.0 (0.0 to 66.7)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Pain in Arm and Shoulder

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    End point title
    		 HRQoL by EORTC Quality of Life Questionnaire LC13 Score Pain in Arm and Shoulder
    End point description
    The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
    End point type
    Secondary
    End point timeframe
    Baseline, every 4 weeks until disease progression (up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Score on a scale
    median (full range (min-max))
        Baseline (n=100, 96)
    0.0 (0.0 to 100.0)
    0.0 (0.0 to 100.0)
        Treatment - Week 4 (n=95, 89)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 100.0)
        Treatment - Week 8 (n=89, 84)
    0.0 (0.0 to 100.0)
    0.0 (0.0 to 66.7)
        Treatment - Week 12 (n=75, 78)
    0.0 (0.0 to 100.0)
    0.0 (0.0 to 66.7)
        Treatment - Week 16 (n=79, 73)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 20 (n=73, 67)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 24 (n=77, 71)
    0.0 (0.0 to 33.3)
    0.0 (0.0 to 66.7)
        Treatment - Week 28 (n=67, 62)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 32 (n=73, 65)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 100.0)
        Treatment - Week 36 (n=64, 61)
    0.0 (0.0 to 100.0)
    0.0 (0.0 to 66.7)
        Treatment - Week 40 (n=74, 50)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 100.0)
        Treatment - Week 44 (n=62, 47)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 100.0)
        Treatment - Week 48 (n=67, 47)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 52 (n=58, 44)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 56 (n=61, 48)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 60 (n=47, 39)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 64 (n=55, 39)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 68 (n=49, 34)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 72 (n=54, 34)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 76 (n=42, 29)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 80 (n=43, 23)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 84 (n=33, 19)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 88 (n=36, 16)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 92 (n=30, 13)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 100.0)
        Treatment - Week 96 (n=22, 11)
    33.33 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 100 (n=18, 10)
    33.33 (0.0 to 66.7)
    0.0 (0.0 to 66.7)
        Treatment - Week 104 (n=15, 7)
    33.33 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 108 (n=11, 7)
    0.0 (0.0 to 66.7)
    0.0 (0.0 to 33.3)
        Treatment - Week 112 (n=9, 4)
    0.0 (0.0 to 66.7)
    16.67 (0.0 to 33.33)
        Treatment - Week 116 (n=4, 2)
    16.67 (0.0 to 33.33)
    16.67 (0.0 to 33.33)
        Treatment - Week 120 (n=3, 0)
    33.33 (33.33 to 33.33)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with PFS event by IRC

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    End point title
    		 Percentage of Participants with PFS event by IRC
    End point description
    PFS was assessed as percentage of participants with disease progression or death whichever occurred first by IRC assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm and the appearance of new lesions.
    End point type
    Secondary
    End point timeframe
    Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Percentage of Participants
        number (not applicable)
    41.4
    60.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Central Nervous System (CNS) Progression as Determined by IRC Using Revised Assessment in Neuro Oncology (RANO) Criteria

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    End point title
    		 Percentage of Participants with Central Nervous System (CNS) Progression as Determined by IRC Using Revised Assessment in Neuro Oncology (RANO) Criteria
    End point description
    CNS progression was assessed as percentage of participants with event defined as time from randomization until first radiographic evidence of CNS progression by IRC. The risk for a CNS progression without a prior non-CNS progression with alectinib compared with crizotinib.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression in the CNS (assessed every 8 weeks up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Percentage of participants
        number (not applicable)
    10.5
    35.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants with OS event

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    End point title
    		 Percentage of Participants with OS event
    End point description
    Overall survival (OS) was defined as the time from randomization to death from any cause.
    End point type
    Secondary
    End point timeframe
    From randomization until death (up to 43 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Percentage of participants
        number (not applicable)
    23.0
    26.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Deterioration by EORTC Quality Of Life Questionnaire Core 30 (C30)

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    End point title
    		 Percentage of Participants with Deterioration by EORTC Quality Of Life Questionnaire Core 30 (C30)
    End point description
    The EORTC QLQ-30 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in global health status or function is defined as a >or=10-point decrease from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point decrease from baseline followed by death within 5 weeks from the last assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, every 4 weeks until disease progression (up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Percentage of participants
    number (not applicable)
        Fatigue
    21.7
    25.2
        Dyspnea
    17.1
    9.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Deterioration by EORTC Quality of Life Questionnaire Lung Cancer Module 13 (LC13)

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    End point title
    		 Percentage of Participants with Deterioration by EORTC Quality of Life Questionnaire Lung Cancer Module 13 (LC13)
    End point description
    The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in lung cancer symptoms is defined as a >or=10-point increase from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point increase above baseline followed by death within 5 weeks from the last assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, every 4 weeks until disease progression (up to 33 months)
    End point values
    		 Experimental: Alectinib Comparator: Crizotinib
    Number of subjects analysed
    152
    151
    Units: Percentage of participants
    number (not applicable)
        Coughing
    11
    11
        Dyspnea
    28
    16
        Pain in arm and shoulder
    18
    12
        Pain in chest
    7
    11
        Composite score (c, p in c, d)
    32
    28
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 43 months
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Alectinib
    Reporting group description
    		 Subjects received alectinib at 600 mg orally BID from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Reporting group title
    Crizotinib
    Reporting group description
    		 Subjects received crizotinib at 250 mg orally BID from Visit 0 (baseline) until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Serious adverse events
    		 Alectinib Crizotinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 152 (28.95%)
    45 / 151 (29.80%)
         number of deaths (all causes)
    35
    40
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ovarian Cancer
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 152 (0.00%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic Hypotension
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 152 (0.66%)
    3 / 151 (1.99%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Discomfort
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia Malignant
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chest Pain
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine Polyp
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    2 / 152 (1.32%)
    4 / 151 (2.65%)
         occurrences causally related to treatment / all
    1 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumothorax
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 152 (1.32%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary Embolism
         subjects affected / exposed
    2 / 152 (1.32%)
    3 / 151 (1.99%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopleural Fistula
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Haemorrhage
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Interstitial Lung Disease
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    1 / 152 (0.66%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood Creatinine Increased
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 152 (0.66%)
    4 / 151 (2.65%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human Chorionic Gonadotropin Increased
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Forearm Fracture
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic Vertebral Fracture
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Myocardial Infarction
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus Bradycardia
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Tamponade
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (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
    Aphasia
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Haemorrhage
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage Intracranial
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Coma
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vision Blurred
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 152 (0.00%)
    3 / 151 (1.99%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 152 (0.00%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Disorder
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug−Induced Liver Injury
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Haematoma
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Haemorrhage
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (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
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Impairment
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Kidney Injury
         subjects affected / exposed
    4 / 152 (2.63%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary Retention
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         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
    1 / 152 (0.66%)
    0 / 151 (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
    Pneumonia
         subjects affected / exposed
    5 / 152 (3.29%)
    4 / 151 (2.65%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    3 / 152 (1.97%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acinetobacter Infection
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising Fasciitis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal Candidiasis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Klebsiella
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 Alectinib Crizotinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    136 / 152 (89.47%)
    140 / 151 (92.72%)
    General disorders and administration site conditions
    Oedema Peripheral
         subjects affected / exposed
    26 / 152 (17.11%)
    41 / 151 (27.15%)
         occurrences all number
    30
    49
    Fatigue
         subjects affected / exposed
    29 / 152 (19.08%)
    25 / 151 (16.56%)
         occurrences all number
    34
    25
    Asthenia
         subjects affected / exposed
    11 / 152 (7.24%)
    11 / 151 (7.28%)
         occurrences all number
    13
    12
    Pyrexia
         subjects affected / exposed
    7 / 152 (4.61%)
    9 / 151 (5.96%)
         occurrences all number
    7
    10
    Chest Pain
         subjects affected / exposed
    9 / 152 (5.92%)
    5 / 151 (3.31%)
         occurrences all number
    11
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 152 (7.24%)
    9 / 151 (5.96%)
         occurrences all number
    16
    11
    Dyspnoea
         subjects affected / exposed
    8 / 152 (5.26%)
    6 / 151 (3.97%)
         occurrences all number
    9
    7
    Productive Cough
         subjects affected / exposed
    8 / 152 (5.26%)
    1 / 151 (0.66%)
         occurrences all number
    9
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 152 (9.87%)
    9 / 151 (5.96%)
         occurrences all number
    15
    9
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    22 / 152 (14.47%)
    42 / 151 (27.81%)
         occurrences all number
    31
    49
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    20 / 152 (13.16%)
    37 / 151 (24.50%)
         occurrences all number
    30
    46
    Blood Bilirubin Increased
         subjects affected / exposed
    23 / 152 (15.13%)
    2 / 151 (1.32%)
         occurrences all number
    25
    2
    Blood Creatinine Increased
         subjects affected / exposed
    11 / 152 (7.24%)
    6 / 151 (3.97%)
         occurrences all number
    15
    6
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    8 / 152 (5.26%)
    7 / 151 (4.64%)
         occurrences all number
    10
    10
    Weight Increased
         subjects affected / exposed
    15 / 152 (9.87%)
    0 / 151 (0.00%)
         occurrences all number
    15
    0
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    6 / 152 (3.95%)
    8 / 151 (5.30%)
         occurrences all number
    6
    8
    Gamma−Glutamyltransferase Increased
         subjects affected / exposed
    1 / 152 (0.66%)
    10 / 151 (6.62%)
         occurrences all number
    1
    11
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    8 / 152 (5.26%)
    14 / 151 (9.27%)
         occurrences all number
    8
    14
    Sinus Bradycardia
         subjects affected / exposed
    8 / 152 (5.26%)
    7 / 151 (4.64%)
         occurrences all number
    9
    7
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    4 / 152 (2.63%)
    29 / 151 (19.21%)
         occurrences all number
    4
    33
    Dizziness
         subjects affected / exposed
    12 / 152 (7.89%)
    20 / 151 (13.25%)
         occurrences all number
    16
    21
    Headache
         subjects affected / exposed
    11 / 152 (7.24%)
    13 / 151 (8.61%)
         occurrences all number
    12
    16
    Paraesthesia
         subjects affected / exposed
    3 / 152 (1.97%)
    8 / 151 (5.30%)
         occurrences all number
    3
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    29 / 152 (19.08%)
    7 / 151 (4.64%)
         occurrences all number
    34
    7
    Neutropenia
         subjects affected / exposed
    4 / 152 (2.63%)
    11 / 151 (7.28%)
         occurrences all number
    4
    24
    Eye disorders
    Visual Impairment
         subjects affected / exposed
    2 / 152 (1.32%)
    18 / 151 (11.92%)
         occurrences all number
    2
    19
    Vision Blurred
         subjects affected / exposed
    3 / 152 (1.97%)
    10 / 151 (6.62%)
         occurrences all number
    3
    11
    Photopsia
         subjects affected / exposed
    0 / 152 (0.00%)
    9 / 151 (5.96%)
         occurrences all number
    0
    11
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    52 / 152 (34.21%)
    49 / 151 (32.45%)
         occurrences all number
    61
    53
    Nausea
         subjects affected / exposed
    21 / 152 (13.82%)
    70 / 151 (46.36%)
         occurrences all number
    23
    83
    Diarrohea
         subjects affected / exposed
    18 / 152 (11.84%)
    68 / 151 (45.03%)
         occurrences all number
    26
    100
    Vomiting
         subjects affected / exposed
    11 / 152 (7.24%)
    57 / 151 (37.75%)
         occurrences all number
    16
    73
    Abdominal Pain
         subjects affected / exposed
    9 / 152 (5.92%)
    7 / 151 (4.64%)
         occurrences all number
    9
    10
    Dyspepsia
         subjects affected / exposed
    5 / 152 (3.29%)
    12 / 151 (7.95%)
         occurrences all number
    5
    13
    Abdominal Pain Upper
         subjects affected / exposed
    8 / 152 (5.26%)
    6 / 151 (3.97%)
         occurrences all number
    8
    6
    Dysphagia
         subjects affected / exposed
    1 / 152 (0.66%)
    8 / 151 (5.30%)
         occurrences all number
    1
    11
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    16 / 152 (10.53%)
    14 / 151 (9.27%)
         occurrences all number
    18
    15
    Alopecia
         subjects affected / exposed
    1 / 152 (0.66%)
    11 / 151 (7.28%)
         occurrences all number
    1
    11
    Photosensitivity Reaction
         subjects affected / exposed
    8 / 152 (5.26%)
    0 / 151 (0.00%)
         occurrences all number
    10
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 152 (11.18%)
    10 / 151 (6.62%)
         occurrences all number
    24
    10
    Myalgia
         subjects affected / exposed
    24 / 152 (15.79%)
    3 / 151 (1.99%)
         occurrences all number
    24
    3
    Back Pain
         subjects affected / exposed
    12 / 152 (7.89%)
    7 / 151 (4.64%)
         occurrences all number
    12
    7
    Pain In Extremity
         subjects affected / exposed
    6 / 152 (3.95%)
    10 / 151 (6.62%)
         occurrences all number
    7
    11
    Musculoskeletal Pain
         subjects affected / exposed
    11 / 152 (7.24%)
    3 / 151 (1.99%)
         occurrences all number
    14
    3
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    13 / 152 (8.55%)
    13 / 151 (8.61%)
         occurrences all number
    17
    17
    Urinary Tract Infection
         subjects affected / exposed
    10 / 152 (6.58%)
    7 / 151 (4.64%)
         occurrences all number
    14
    8
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    14 / 152 (9.21%)
    14 / 151 (9.27%)
         occurrences all number
    14
    20

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Oct 2014
    Protocol version 2 The protocol was amended to comply with questions addressed during the assessment of the Voluntary Harmonisation Procedure VHP444 (VHP201415), Western Institutional Review Board request (dated June 5, 2014) to further specify protocol inclusion criterion, FDA request (dated July 10, 2014) to revise crizotinib dose modification criteria for non-hematologic toxicities to conform to the most recent FDA⎯approved label, as well as feedback from various other Health Authorities/Ethic Committees. Protocol BO28984 was amended to include the latest clinical and safety information.
    14 May 2015
    Protocol version 3 The protocol was amended to incorporate the latest pre-clinical and safety information. Changes include those to the specific timing of dose administration, pharmacokinetic objectives, concomitant therapy, and exploratory objectives.
    15 Apr 2016
    Protocol version 4 The protocol was amended to incorporate the latest safety and drug administration information. Changes include those to adverse events (AEs) relating to alectinib data and management of alectinib AEs guidelines, restrictions related to QT-prolonging concomitant medications for alectinib, and guideline for the management of missing doses of alectinib.

    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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