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    Clinical Trial Results:
    Randomised, multicenter, Phase III, open-label study of alectinib versus pemetrexed or docetaxel in anaplastic lymphoma kinase-positive advanced non-small cell lung cancer patients previously treated with platinum-based chemotherapy and crizotinib.

    Summary
    EudraCT number
    		 2015-000634-29
    Trial protocol
    		 PT   ES   DE   SK   HU   FR   PL   BE   BG   IT  
    Global end of trial date
    13 Aug 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    22 Aug 2019
    First version publication date
    09 Feb 2018
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    The study has completed and this update contains the full data set, including data collected after the first results upload to EudraCT.

    Trial information

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    Trial identification
    Sponsor protocol code
    MO29750
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02604342
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Acronym: ALUR
    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
    F. Hoffmann-La Roche AG, 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
    Final
    Date of interim/final analysis
    13 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to evaluate and compare between treatment groups the efficacy of alectinib versus chemotherapy in subjects with ALK-positive advanced NSCLC who were previously treated with chemotherapy and crizotinib (progressed or intolerant to crizotinib), 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
    03 Nov 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hong Kong: 5
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 38
    Country: Number of subjects enrolled
    Norway: 8
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Turkey: 14
    Worldwide total number of subjects
    119
    EEA total number of subjects
    85
    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)
    92
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study recruited subjects with Anaplastic Lymphoma Kinase(ALK)-positive advanced Non-Small Cell Lung Cancer(NSCLC) in 13 countries from November 2015 to January 2017.

    Pre-assignment
    Screening details
    		 A total of 142 subjects were screened, of which 119 were enrolled, 79 subjects in the alectinib arm and 40 in the chemotherapy 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 oral alectinib at a dose of 600 milligrams (mg) twice daily, taken with food and treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alectinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received oral alectinib at a dose of 600 mg twice daily, taken with food until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Arm title
    		 Active Comparator: Premetrexed/Docetaxel
    Arm description
    		 Subjects received chemotherapy with either pemetrexed (500 milligrams per square meter [mg/m^2] of body surface area) or docetaxel (75 mg/m^2) intravenously.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Taxotere®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received docetaxel at a dose of 75 mg/m^2 of body surface area intravenously every 3 weeks, until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Investigational medicinal product name
    Premetrexed
    Investigational medicinal product code
    Other name
    Alimta®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received pemetrexed at a dose of 500 mg/m^2 of body surface area intravenously every 3 weeks, until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Number of subjects in period 1
    		Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Started
    79
    40
    Completed
    36
    17
    Not completed
    43
    23
         Progression disease
    1
    -
         Physician decision
    2
    -
         Death
    32
    16
         Not specified
    1
    -
         Study termination by sponsor
    1
    -
         Lost to follow-up
    1
    1
         Withdrawal by subject
    5
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental: Alectinib
    Reporting group description
    		 Subjects received oral alectinib at a dose of 600 milligrams (mg) twice daily, taken with food and treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Reporting group title
    Active Comparator: Premetrexed/Docetaxel
    Reporting group description
    		 Subjects received chemotherapy with either pemetrexed (500 milligrams per square meter [mg/m^2] of body surface area) or docetaxel (75 mg/m^2) intravenously.

    Reporting group values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel Total
    Number of subjects
    		 79 40 119
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.6 ± 13.0 58.8 ± 10.5 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 33 20 53
        Male
    		 46 20 66
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 5 4 9
        Not Hispanic or Latino
    		 68 34 102
        Not reported
    		 4 1 5
        Unknown
    		 0 1 1
        Missing
    		 2 0 2
    Race
    Units: Subjects
        White
    		 67 32 99
        Asian
    		 6 8 14
        Unknown
    		 5 0 5
        Native Hawaiian or other Pacific Islander
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Experimental: Alectinib
    Reporting group description
    		 Subjects received oral alectinib at a dose of 600 milligrams (mg) twice daily, taken with food and treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Reporting group title
    Active Comparator: Premetrexed/Docetaxel
    Reporting group description
    		 Subjects received chemotherapy with either pemetrexed (500 milligrams per square meter [mg/m^2] of body surface area) or docetaxel (75 mg/m^2) intravenously.

    Primary: Progression-Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator

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    End point title
    		 Progression-Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator
    End point description
    PFS was defined as the time from randomisation to the first documented disease progression, as determined using RECIST v1.1, or death from any cause, whichever occurred first. 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. ITT population included all subjects randomised in the study, irrespective of whether or not they received study drug.
    End point type
    Primary
    End point timeframe
    Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    79
    40
    Units: months
        median (confidence interval 95%)
    10.9 (8.1 to 15.5)
    1.4 (1.2 to 1.6)
    Statistical analysis title
    		 Alectinib vs Premetrexed/Docetaxel
    Statistical analysis description
    Estimated hazard ratio obtained from stratified Cox model with treatment group as covariate.
    Comparison groups
    Experimental: Alectinib v Active Comparator: Premetrexed/Docetaxel
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 0.33

    Secondary: Percentage of Subjects With CNS Objective Response Rate (C-ORR) With Measurable CNS Metastases at Baseline Using RECIST Version 1.1 as Assessed By IRC

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    End point title
    		 Percentage of Subjects With CNS Objective Response Rate (C-ORR) With Measurable CNS Metastases at Baseline Using RECIST Version 1.1 as Assessed By IRC
    End point description
    Overall response rate in subjects with confirmed CNS response (C-ORR) was defined as the percentage of subjects who attained Complete Response (CR) or Partial Response (PR) for lesions in the CNS. 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. Intent-to-treat population with measurable CNS metastasis (mC-ITT) included all subjects in ITT population with measurable CNS metastasis at baseline (as per IRC).
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    24
    17
    Units: percentage of subjects
        number (not applicable)
    66.7
    0.0
    Statistical analysis title
    		 C-ORR
    Statistical analysis description
    95% confidence interval of the difference (alectinib - chemotherapy) computed using Hauck-Anderson approach.
    Comparison groups
    Experimental: Alectinib v Active Comparator: Premetrexed/Docetaxel
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Parameter type
    		 Difference in C-ORR
    Point estimate
    0.667
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.86

    Secondary: PFS Using RECIST Version 1.1 as Assessed by IRC

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    End point title
    		 PFS Using RECIST Version 1.1 as Assessed by IRC
    End point description
    PFS was defined as the time from randomisation to the first documented disease progression, as determined using RECIST v1.1, or death from any cause, whichever occurred first. 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. ITT population included all subjects randomised in the study, irrespective of whether or not they received study drug. This outcome measure was assessed as part of the primary analysis and was not repeated during final analysis.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    72
    35
    Units: months
        median (confidence interval 95%)
    7.1 (6.3 to 10.8)
    1.6 (1.3 to 4.1)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Objective Response of CR or PR Using RECIST Version 1.1 as Assessed by Investigator and IRC

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    End point title
    		 Percentage of Subjects with Objective Response of CR or PR Using RECIST Version 1.1 as Assessed by Investigator and IRC
    End point description
    ORR was defined as the percentage of subjects 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. ITT population included all subjects randomised in the study, irrespective of whether or not they received study drug. The IRC assessment was part of the primary analysis and was not repeated during final analysis.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    79
    40
    Units: percentage of subjects
    number (not applicable)
        Assessed by Investigator
    50.6
    2.5
        Assessed by IRC (n=72, 35)
    36.1
    11.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Disease Control Using RECIST Version 1.1 as Assessed by Investigator and IRC

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    End point title
    		 Percentage of Subjects with Disease Control Using RECIST Version 1.1 as Assessed by Investigator and IRC
    End point description
    Disease control rate (DCR) was defined as the percentage of subjects who attained CR, PR, or stable disease (SD) of at least 5 weeks. 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, SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters since the treatment started. ITT population included all subjects randomised in the study, irrespective of whether or not they received study drug. The IRC assessment was part of the primary analysis and was not repeated during final analysis.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    79
    40
    Units: percentage of subjects
    number (not applicable)
        Assessed by Investigator
    86.1
    25.0
        Assessed by IRC
    76.4
    48.6
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Using RECIST Version 1.1 as Assessed by Investigator and IRC

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    End point title
    		 Duration of Response (DOR) Using RECIST Version 1.1 as Assessed by Investigator and IRC
    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 subjects who had a best overall response (BOR) of CR or PR. ITT population included all subjects randomised in the study, irrespective of whether or not they received study drug. Here, "99999" indicates that the median and confidence interval was not reached due to less number of subjects with the event. The IRC assessment was part of the primary analysis and was not repeated during final analysis.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (Tumor assessments at baseline, every 6 weeks until PD, death or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    40
    1
    Units: months
    median (confidence interval 95%)
        Assessed by Investigator (n= 40, 1)
    12.0 (8.3 to 23.5)
    2.7 (-99999 to 99999)
        Assessed by IRC (n= 26, 4)
    9.7 (5.6 to 99999)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: PFS in C-ITT Population Using RECIST Version 1.1 as Assessed by Investigator and IRC

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    End point title
    		 PFS in C-ITT Population Using RECIST Version 1.1 as Assessed by Investigator and IRC
    End point description
    PFS was defined as the time from randomisation to the first documented disease progression, as determined using RECIST v1.1, or death from any cause, whichever occurred first. 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. Intent-to-treat population with CNS metastasis (C-ITT) included subjects in ITT population with CNS metastasis at baseline (as per IRC assessment). Here, "99999" indicates that the upper limit of confidence interval was not reached due to less number of subjects with the event. This outcome measure assessment was part of the primary analysis and was not repeated during final analysis.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    50
    26
    Units: months
    median (confidence interval 95%)
        Assessed by Investigator
    9.7 (6.9 to 99999)
    1.4 (1.2 to 1.6)
        Assessed by IRC
    8.1 (6.3 to 99999)
    1.5 (1.2 to 4.1)
    No statistical analyses for this end point

    Secondary: Time to CNS progression in C-ITT Population Using RECIST Version 1.1 as Assessed by IRC

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    End point title
    		 Time to CNS progression in C-ITT Population Using RECIST Version 1.1 as Assessed by IRC
    End point description
    Time to CNS progression was defined as the time from randomisation until radiographic evidence of CNS progression.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. C-ITT included subjects in ITT population with CNS metastasis at baseline (as per IRC assessment). Here, "99999" indicates that the median and upper limit of confidence interval was not reached due to less number of subjects with the event. This outcome measure assessment was part of the primary analysis and was not repeated during final analysis.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    50
    26
    Units: months
        median (confidence interval 95%)
    99999 (6.8 to 99999)
    1.6 (1.3 to 9.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Disease Control in C-ITT Population Using RECIST Version 1.1 as Assessed by IRC

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    End point title
    		 Percentage of Participants With Disease Control in C-ITT Population Using RECIST Version 1.1 as Assessed by IRC
    End point description
    DCR was defined as the percentage of subjects who attained CR, PR, or stable disease (SD) of at least 5 weeks. 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, SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters since the treatment started. C-ITT included subjects in ITT population with CNS metastasis at baseline (as per IRC assessment).
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    52
    28
    Units: percentage of subjects
        number (not applicable)
    82.7
    25.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With ORR in C-ITT Population Using RECIST Version 1.1 as Assessed by IRC

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    End point title
    		 Percentage of Subjects With ORR in C-ITT Population Using RECIST Version 1.1 as Assessed by IRC
    End point description
    ORR was defined as the percentage of subjects 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. C-ITT included participants in ITT population with CNS metastasis at baseline (as per IRC assessment).
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    52
    28
    Units: percentage of subjects
        number (not applicable)
    48.1
    0
    No statistical analyses for this end point

    Secondary: Duration of Response for lesions in the CNS (C-DOR) Using RECIST Version 1.1 as Assessed by IRC

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    End point title
    		 Duration of Response for lesions in the CNS (C-DOR) Using RECIST Version 1.1 as Assessed by IRC
    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. C-DOR was defined in a similar way for lesions in the CNS, taking into account all lesions in the body. DOR was evaluated for subjects who had a BOR of CR or PR. C-ITT included subjects in ITT population with CNS metastasis at baseline (as per IRC assessment). Here, "99999" indicates that the median and upper limit of confidence interval was not reached due to less number of subjects with the event.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    52 [1]
    28 [2]
    Units: months
        median (confidence interval 95%)
    13.9 (6.2 to 13.9)
    99999 (99999 to 99999)
    Notes
    [1] - Number of subjects with CR or PR
    [2] - Number of subjects with CR or PR
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomisation to death from any cause. OS was confounded by cross-over of subjects to the alectinib arm. ITT population included all subjects randomised in the study, irrespective of whether or not they received study drug. Here, "99999" indicates that the median and confidence interval was not reached due to less number of subjects with the event.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (Baseline until death)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    79
    40
    Units: months
        median (confidence interval 95%)
    27.8 (18.2 to 99999)
    99999 (8.6 to 99999)
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Alectinib

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    End point title
    		 Plasma Concentration of Alectinib [3]
    End point description
    The Pharmacokinetic (PK) Evaluable Population included all subjects who received any dose of alectinib and who had at least one post-baseline PK sample available.
    End point type
    Secondary
    End point timeframe
    Predose (2 hours) at Baseline, Week 3 and Week 6
    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: No formal hypothesis testing was planned for this study.
    End point values
    		 Experimental: Alectinib
    Number of subjects analysed
    56
    Units: nanogram/milliliter (ng/mL)
        geometric mean (geometric coefficient of variation)
    559 ± 48.0
    No statistical analyses for this end point

    Secondary: Compliance of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) Over Time

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    End point title
    		 Compliance of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) Over Time
    End point description
    Percentage of subjects who filled out an EORTC QLQ-C30 questionnaire at a visit. 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. ITT population included all subjects randomised in the study, irrespective of whether or not they received study drug. 99999 indicates that data was not collected as no subject was evaluated at the specified time point.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (baseline, Weeks 3, 6, 12 and every 6 weeks until PD, death, or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    79
    40
    Units: percentage of subjects
    number (not applicable)
        Baseline
    92.4
    85.0
        Treatment - Week 3
    96.1
    83.3
        Treatment - Week 6
    97.2
    60.0
        Treatment - Week 12
    95.5
    80.0
        Treatment - Week 18
    88.5
    50.0
        Treatment - Week 24
    91.1
    100
        Treatment - Week 30
    96.2
    66.7
        Treatment - Week 36
    89.8
    66.7
        Treatment - Week 42
    100
    50
        Treatment - Week 48
    100
    100
        Treatment - Week 54
    97.1
    100
        Treatment - Week 60
    100
    100
        Treatment - Week 66
    89.7
    100
        Treatment - Week 72
    88.9
    100
        Treatment - Week 78
    84.6
    99999
        Treatment - Week 84
    78.3
    99999
        Treatment - Week 90
    88.9
    99999
        Treatment - Week 96
    93.8
    99999
        Treatment - Week 102
    84.6
    99999
        Treatment - Week 108
    100
    99999
        Treatment - Week 114
    83.3
    99999
        Treatment - Week 120
    100
    99999
        Treatment - Week 126
    100
    99999
        Treatment - Week 132
    100
    99999
        Treatment - Week 138
    100
    99999
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Alectinib Metabolite

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    End point title
    		 Plasma Concentration of Alectinib Metabolite [4]
    End point description
    The PK Evaluable Population included all subjects who received any dose of alectinib and who had at least one post-baseline PK sample available.
    End point type
    Secondary
    End point timeframe
    Predose (2 hours) at Baseline, Week 3 and Week 6
    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: No formal hypothesis testing was planned for this study.
    End point values
    		 Experimental: Alectinib
    Number of subjects analysed
    56
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    240 ± 44.8
    No statistical analyses for this end point

    Secondary: Compliance of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer-13 (EORTC QLQ-LC13) Over Time

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    End point title
    		 Compliance of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer-13 (EORTC QLQ-LC13) Over Time
    End point description
    Percentage of subjects who filled out an EORTC QLQ-LC13 questionnaire at a visit. 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. ITT population included all subjects randomised in the study, irrespective of whether or not they received study drug. 99999 indicates that data was not collected as no subject was evaluated at the specified time point.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (baseline, Weeks 3, 6, 12 and every 6 weeks until PD, death, or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    79
    40
    Units: percentage of subjects
    number (not applicable)
        Baseline
    92.4
    82.5
        Treatment - Week 3
    96.1
    83.3
        Treatment - Week 6
    97.2
    63.3
        Treatment - Week 12
    95.5
    80.0
        Treatment - Week 18
    88.5
    50.0
        Treatment - Week 24
    91.1
    100
        Treatment - Week 30
    96.2
    66.7
        Treatment - Week 36
    87.8
    66.7
        Treatment - Week 42
    95.3
    66.7
        Treatment - Week 48
    100
    100
        Treatment - Week 54
    97.1
    100
        Treatment - Week 60
    100
    100
        Treatment - Week 66
    89.7
    100
        Treatment - Week 72
    88.9
    100
        Treatment - Week 78
    84.6
    99999
        Treatment - Week 84
    78.3
    99999
        Treatment - Week 90
    88.9
    99999
        Treatment - Week 96
    100
    99999
        Treatment - Week 102
    84.6
    99999
        Treatment - Week 108
    100
    99999
        Treatment - Week 114
    83.3
    99999
        Treatment - Week 120
    80.0
    99999
        Treatment - Week 126
    100
    99999
        Treatment - Week 132
    100
    99999
        Treatment - Week 138
    100
    99999
    No statistical analyses for this end point

    Secondary: Compliance of European Quality of Life (EuroQoL) 5 Dimension 5 Levels (EQ-5D-5L) Questionnaire Over Time

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    End point title
    		 Compliance of European Quality of Life (EuroQoL) 5 Dimension 5 Levels (EQ-5D-5L) Questionnaire Over Time
    End point description
    Percentage of subjects who filled out an EQ-5D-5L questionnaire at a visit. EQ-5D-5L: A generic preference-based health utility measure that provides a single index value for health status. The instrument consists of two parts. The first part, health-state classification, contains five dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. ITT population included all subjects randomised in the study, irrespective of whether or not they received study drug. "n" indicates number of subjects evaluated for specified time points. Here, "99999" indicates that the mean and standard deviation was not reached due to less number of subjects evaluated and no subject was evaluated for some time points.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (baseline, Weeks 3, 6, 12 and every 6 weeks until PD, death, or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    72
    35
    Units: percentage of subjects
    number (not applicable)
        Treatment - Week 0 (n=72,35)
    88.9
    82.9
        Treatment - Week 3 (n=67,33)
    86.6
    78.8
        Treatment - Week 6 (n=62,29)
    91.9
    58.6
        Treatment - Week 12 (n=53,10)
    86.8
    80
        Treatment - Week 18 (n=43,6)
    72.1
    66.7
        Treatment - Week 24 (n=34,3)
    82.4
    100
        Treatment - Week 30 (n=25,3)
    80
    66.7
        Treatment - Week 36 (n=20,2)
    80
    50
        Treatment - Week 42 (n=12,2)
    91.7
    50
        Treatment - Week 48 (n=8,1)
    62.5
    0
        Treatment - Week 54 (n=3,0)
    3
    99999
        Treatment - Week 60 (n=2,0)
    1
    99999
    No statistical analyses for this end point

    Secondary: Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC13 Score for ITT Population

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    End point title
    		 Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC13 Score for ITT Population
    End point description
    TTD in the overall population is defined as time from randomization to the earliest time with a ≥10-point increase from baseline for symptoms domains (or decrease for functioning domains from baseline for cough, dyspnea [single item and multi-item scales] chest pain [single item], pain in arm/shoulder and fatigue as measured by the EORTC QLQ-LC13. ITT population included all subjects randomised in the study, irrespective of whether or not they received study drug. "n" indicates number of subjects evaluated for specified categories. Here, "99999" indicates that the median and confidence interval was not reached due to less number of subjects with the event.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (baseline, Weeks 3, 6, 12 and every 6 weeks until PD, death, or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    79
    40
    Units: months
    median (confidence interval 95%)
        Coughing score
    18.1 (7.2 to 99999)
    16.6 (3.3 to 16.6)
        Dyspnoea score
    4.1 (1.4 to 11.3)
    3.3 (1.0 to 99999)
        Pain in chest score
    99999 (11.1 to 99999)
    99999 (1.6 to 99999)
        Pain in arm or shoulder score
    12.5 (7.4 to 99999)
    1.9 (1.6 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC13 Score for C-ITT Population

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    End point title
    		 Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC13 Score for C-ITT Population
    End point description
    TTD in the overall population is defined as time from randomization to the earliest time with a ≥10-point increase from baseline for symptoms domains (or decrease for functioning domains from baseline for cough, dyspnea [single item and multi-item scales] chest pain [single item], pain in arm/shoulder and fatigue as measured by the EORTC QLQ-LC13. C-ITT included subjects in ITT population with CNS metastasis at baseline (as per IRC assessment). "n" indicates the number of subjects evaluated for specified categories. Here, "99999" indicates that the median and confidence interval was not reached due to less number of subjects with the event.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (baseline, Weeks 3, 6, 12 and every 6 weeks until PD, death, or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    52
    28
    Units: months
    median (confidence interval 95%)
        Coughing score
    99999 (8.3 to 99999)
    16.6 (1.2 to 16.6)
        Dyspnoea score
    9.7 (1.5 to 14.4)
    1.4 (0.8 to 99999)
        Pain in chest score
    99999 (9.7 to 99999)
    99999 (1.4 to 99999)
        Pain in arm or shoulder score
    11.1 (4.1 to 99999)
    1.7 (0.9 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC30 Score for ITT Population

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    End point title
    		 Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC30 Score for ITT Population
    End point description
    TTD in the overall population is defined as time from randomization to the earliest time with a ≥10-point increase from baseline for symptoms domains (or decrease for functioning domains from baseline for cough, dyspnea [single item and multi-item scales] chest pain [single item], pain in arm/shoulder and fatigue as measured by the EORTC QLQ-C30. ITT population included all subjects randomised in the study, irrespective of whether or not they received study drug. Here, "99999" indicates that the median and upper limit of confidence interval was not reached because of less number of subjects with the event.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (baseline, Weeks 3, 6, 12 and every 6 weeks until PD, death, or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    79
    40
    Units: months
    median (confidence interval 95%)
        Dyspnoea score
    13.3 (2.9 to 99999)
    8.3 (1.2 to 8.3)
        Fatigue score
    5.6 (1.4 to 99999)
    1.2 (0.8 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC30 Score for C-ITT Population

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    End point title
    		 Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC30 Score for C-ITT Population
    End point description
    TTD in the overall population is defined as time from randomization to the earliest time with a ≥10-point increase from baseline for symptoms domains (or decrease for functioning domains from baseline for cough, dyspnea [single item and multi-item scales] chest pain [single item], pain in arm/shoulder and fatigue as measured by the EORTC QLQ-C30. C-ITT included subjects in ITT population with CNS metastasis at baseline (as per IRC assessment). Here, "99999" indicates that the median and upper limit of confidence interval was not reached because of less number of subjects with the event.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (baseline, Weeks 3, 6, 12 and every 6 weeks until PD, death, or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    52
    26
    Units: months
    median (confidence interval 95%)
        Dyspnoea score
    16.6 (2.9 to 99999)
    8.3 (1.0 to 8.3)
        Fatigue score
    14.4 (2.6 to 99999)
    1.0 (0.8 to 99999)
    No statistical analyses for this end point

    Secondary: TTD in Composite of Three Symptoms (Cough, Dyspnea, and Chest Pain) Using EORTC QLQ-LC13 Score for C-ITT Population

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    End point title
    		 TTD in Composite of Three Symptoms (Cough, Dyspnea, and Chest Pain) Using EORTC QLQ-LC13 Score for C-ITT Population
    End point description
    TTD for a composite of three symptoms (cough, dyspnea, chest pain) in the overall population is defined as time from randomization to the earliest time with a ≥10-point increase from baseline for any component of the composite of the three following symptoms [cough, dyspnea [multi-item subscales QLQ-LC13] and chest pain]) as measured by the EORTC QLQ-LC13. C-ITT included subjects in ITT population with CNS metastasis at baseline (as per IRC assessment). Here, "99999" indicates that the upper limit of confidence interval was not reached due to less number of subjects with the event.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (baseline, Weeks 3, 6, 12 and every 6 weeks until PD, death, or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    52
    28
    Units: months
        median (confidence interval 95%)
    2.8 (0.9 to 5.6)
    1.4 (0.8 to 99999)
    No statistical analyses for this end point

    Secondary: TTD in Composite of Three Symptoms (Cough, Dyspnea, and Chest Pain) Using EORTC QLQ-LC13 Score for ITT Population

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    End point title
    		 TTD in Composite of Three Symptoms (Cough, Dyspnea, and Chest Pain) Using EORTC QLQ-LC13 Score for ITT Population
    End point description
    TTD for a composite of three symptoms (cough, dyspnea, chest pain) in the overall population is defined as time from randomization to the earliest time with a ≥10-point increase from baseline for any component of the composite of the three following symptoms [cough, dyspnea [multi-item subscales QLQ-LC13] and chest pain]) as measured by the EORTC QLQ-LC13. ITT population included all subjects randomised in the study, irrespective of whether or not they received study drug. Here, "99999" indicates that the upper limit of confidence interval was not reached due to less number of subjects with the event.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months (baseline, Weeks 3, 6, 12 and every 6 weeks until PD, death, or withdrawal from study prior to PD)
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    79
    40
    Units: months
        median (confidence interval 95%)
    1.4 (0.9 to 4.2)
    1.4 (0.9 to 4.2)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Adverse Events (AEs)

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    End point title
    		 Percentage of Subjects with Adverse Events (AEs)
    End point description
    An 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. Safety (SAF) population included all subjects who received at least one dose of any study drug.
    End point type
    Secondary
    End point timeframe
    Approximately 15 months
    End point values
    		 Experimental: Alectinib Active Comparator: Premetrexed/Docetaxel
    Number of subjects analysed
    70
    34
    Units: percentage of subjects
        number (not applicable)
    89.6
    89.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 15 months
    Adverse event reporting additional description
    SAF population included all subjects who received at least one dose of any study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Active Comparator: Premetrexed/Docetaxel
    Reporting group description
    		 Participants received chemotherapy with either pemetrexed (500 milligrams per square meter [mg/m^2] of body surface area) or docetaxel (75 mg/m^2) intravenously.

    Reporting group title
    Experimental: Alectinib
    Reporting group description
    		 Participants received oral alectinib at a dose of 600 milligrams (mg) twice daily, taken with food and treatment discontinued until disease progression, unacceptable toxicity, withdrawal of consent or death.

    Serious adverse events
    		 Active Comparator: Premetrexed/Docetaxel Experimental: Alectinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 37 (18.92%)
    20 / 77 (25.97%)
         number of deaths (all causes)
    4
    26
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         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 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         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
    Death
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fractured base
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar ataxia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoporotic fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess jaw
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 37 (0.00%)
    4 / 77 (5.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Active Comparator: Premetrexed/Docetaxel Experimental: Alectinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 37 (67.57%)
    36 / 77 (46.75%)
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 37 (0.00%)
    6 / 77 (7.79%)
         occurrences all number
    0
    8
    Blood creatinine increased
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 77 (6.49%)
         occurrences all number
    0
    7
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 37 (0.00%)
    4 / 77 (5.19%)
         occurrences all number
    0
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 77 (3.90%)
         occurrences all number
    2
    3
    Headache
         subjects affected / exposed
    3 / 37 (8.11%)
    5 / 77 (6.49%)
         occurrences all number
    3
    6
    Neuropathy peripheral
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 77 (1.30%)
         occurrences all number
    3
    1
    Paraesthesia
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 77 (1.30%)
         occurrences all number
    2
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 37 (10.81%)
    12 / 77 (15.58%)
         occurrences all number
    4
    12
    Neutropenia
         subjects affected / exposed
    4 / 37 (10.81%)
    0 / 77 (0.00%)
         occurrences all number
    4
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 37 (16.22%)
    9 / 77 (11.69%)
         occurrences all number
    6
    14
    Fatigue
         subjects affected / exposed
    9 / 37 (24.32%)
    5 / 77 (6.49%)
         occurrences all number
    10
    7
    Oedema peripheral
         subjects affected / exposed
    2 / 37 (5.41%)
    11 / 77 (14.29%)
         occurrences all number
    2
    11
    Pyrexia
         subjects affected / exposed
    3 / 37 (8.11%)
    3 / 77 (3.90%)
         occurrences all number
    5
    4
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 77 (2.60%)
         occurrences all number
    2
    2
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 37 (10.81%)
    16 / 77 (20.78%)
         occurrences all number
    5
    21
    Vomiting
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 77 (3.90%)
         occurrences all number
    2
    3
    Nausea
         subjects affected / exposed
    6 / 37 (16.22%)
    3 / 77 (3.90%)
         occurrences all number
    8
    4
    Diarrhoea
         subjects affected / exposed
    2 / 37 (5.41%)
    5 / 77 (6.49%)
         occurrences all number
    3
    6
    Abdominal pain
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 77 (6.49%)
         occurrences all number
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 37 (10.81%)
    8 / 77 (10.39%)
         occurrences all number
    5
    9
    Dyspnoea
         subjects affected / exposed
    0 / 37 (0.00%)
    9 / 77 (11.69%)
         occurrences all number
    0
    10
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    8 / 37 (21.62%)
    1 / 77 (1.30%)
         occurrences all number
    8
    1
    Pruritus generalised
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 77 (0.00%)
         occurrences all number
    5
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 37 (5.41%)
    10 / 77 (12.99%)
         occurrences all number
    2
    10
    Myalgia
         subjects affected / exposed
    4 / 37 (10.81%)
    11 / 77 (14.29%)
         occurrences all number
    5
    12
    Pain in extremity
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 77 (2.60%)
         occurrences all number
    2
    2
    Arthralgia
         subjects affected / exposed
    3 / 37 (8.11%)
    4 / 77 (5.19%)
         occurrences all number
    3
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 77 (2.60%)
         occurrences all number
    2
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 37 (2.70%)
    5 / 77 (6.49%)
         occurrences all number
    1
    5
    Pneumonia
         subjects affected / exposed
    0 / 37 (0.00%)
    6 / 77 (7.79%)
         occurrences all number
    0
    7
    Nasopharyngitis
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 77 (5.19%)
         occurrences all number
    1
    5
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 37 (2.70%)
    7 / 77 (9.09%)
         occurrences all number
    1
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 37 (10.81%)
    7 / 77 (9.09%)
         occurrences all number
    4
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Nov 2015
    • Throughout the protocol, a clarification for the timing of first administration of pemetrexed was added, indicating that required premedication for premetrexed administration (and not the study drug itself) was to be started as soon as possible after randomisation; subsequent treatment with study drug could be started according to local practice. In addition the time frame indicated for starting required premedication was changed, and a referral to local practice was added • For the subject-reported outcome (PRO) analysis of TTD, description of the analyses was aligned within the protocol in order to specify the lung cancer symptoms that were to be analyzed. In addition, description of the composite endpoint of three lung cancer symptoms was aligned within the protocol. The rationale for analyzing TTD based on the specified lung cancer symptoms and the composite endpoint was that these were used in the PROFILE 1007 trial, comparing the PRO outcome for subjects receiving crizotinib with subjects receiving chemotherapy. In addition, the symptoms that were to be analyzed were aligned with what was to be observed in the Phase III NCT02075840 ALEX trial • Docetaxel, was updated in order to emphasize that administration of required premedication was to be started as soon as possible after randomisation, followed by administration of docetaxel as per local practice • Description of study was updated to clarify the treatment duration of subjects on either of the two treatment arms, emphasizing that for entering the post progression treatment period (PPTP), receiving either alectinib cross over treatment or treatment beyond progression, a radiological, RECIST v.1.1 based disease progression needs to be documented and that subjects need to fulfill the safety based criteria for receiving alectinib. This needed clarification in order to prevent premature cross over from the chemotherapy arms, which would put the primary endpoint of the study (PFS as per investigator) at risk
    26 Nov 2015
    • Background section on alectinib was updated in order to reflect the most recent efficacy and safety results available from Phase II Studies NCT01871805 and NCT01801111 • Efficacy objectives and inclusion criterion number 2 was changed in order to further specify the subject population for the study. Subjects randomized to the trial had to have progressed on crizotinib or had developed intolerability to crizotinib treatment to be eligible for the trial. The two Phase II trials NCT01871805 and NCT01801111 were both conducted in crizotinib failed subjects. Future approval was to be in this setting, and the results from the current study was intended to support these data • For PRO measures, a sentence was added to indicate that the results from EORTC QOQ-C30, EORTC QLQ-LC13 and EQ-5D-5L questionnaires were analyzed in the overall subject group, as well as in the subgroup of subjects with CNS metastases. Due to the fact that at least 50% of the subject population recruited to the trial would have CNS metastases at baseline, it was important to look in particular at that subgroup to see if the efficacy results seen for this subject group also translated into increased quality of life with regards to general lung cancer symptoms • For the EORTC QLQ-BN20 analysis, in order to have a more detailed understanding of the treatment effect on the quality of life of subjects with CNS metastases, a third question chosen from the BN20 questionnaire was added in accordance with a recommendation from the Study Steering Committee • Inclusion criterion number 2 was updated in order to clarify that the two lines of prior NSCLC treatment required for subject to be eligible for the study needed to have been administered in the advanced or metastatic setting
    26 Nov 2015
    • Inclusion criterion number 12 was modified in order to clarify that not only within 3 days before first dose of study drug a negative pregnancy test be obtained, but also that the results had to be available prior to randomisation in order for the subject to be eligible • Description of Study was updated to clarify details on the PPTP of the trial to include subjects who cross over to receive alectinib upon progression on chemotherapy, and subjects who continue to receive alectinib in treatment beyond progression • Inclusion criterion number 13 was changed to reflect updated guidelines on contraception. For this, reference to double-barrier methods for contraception during the study was removed • Inclusion criterion number 14 was modified to emphasize that the requirement for men to use contraceptive method resulting in a failure rate of less than 1% per year during treatment with study drug and for at least 3 months after permanent discontinuation of study drug but for subjects receiving pemetrexed or docetaxel, local label should be referred to • Secondary Efficacy Endpoints were modified for the secondary endpoint of Time to CNS Progression. In the previous version of the protocol, it was indicated that this would be analyzed using a Kaplan-Meier(KM) estimate and a log-rank test. However due to the competing risks inherent to the analysis of this endpoint, where systemic progression acts as a competing risk for the CNS time to progression, HR and 95% CI and two-sided log-rank test were to be performed on the basis of cause-specific hazard functions was to be used instead to analyze Time to CNS progression. New language was also added to clarify the potential methods that were to be used for assessment of the impact of crossing over to alectinib
    26 Nov 2015
    • Safety Analysis section was updated to reflect that 95% CI was not to be displayed. Reference to the 95% CI was included in previous version of the protocol by error. In addition, new language was added to clarify potential assessments that were to be used to examine safety in subjects who cross over to alectinib following progression on chemotherapy or who continue treatment beyond progression on alectinib
    20 May 2016
    • Change in the risk of hepatobiliary laboratory tests elevations to hepatotoxicity for alectinib, based on following information: 2 subjects with Grade 3-4 aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) elevations had documented drug-induced liver injury by liver biopsy in alectinib pivotal Phase II clinical trials (NCT01871805 and NCT01801111). Concurrent elevations in ALT or AST greater than or equal to three times the upper limit of normal (ULN) and total bilirubin greater than or equal to two times the ULN, with normal ALP, occurred in 1 subject treated in alectinib clinical trials • Change in the monitoring of liver function tests, with more intensive monitoring during the first 3 months of treatment. The majority of transaminase and bilirubin elevations (76% of the subjects with hepatic transaminase elevations and 68% of the subjects with bilirubin elevations) occurred during the first 3 months of treatment, and there were also events, including severe ones, with later onset. As such, monitoring had been intensified and measurements of liver function tests had been added at Weeks 2, 4, 8, 10, and 12 for subjects in the alectinib arm • Change in the risk of muscular AEs and creatine phosphokinase (CPK) elevations to severe myalgia and CPK elevations for alectinib, based on following information: Grade 3 myalgia and CPK elevations had been reported with alectinib treatment and were reversible upon dose reduction and interruption • Change in the monitoring of CPK, with more intensive monitoring during the first month of treatment (added Week 2 and Week 4 measurement of CPK for subjects in the alectinib arm) since median time to Grade 3 CPK elevation was 14 days (interquartile range: 13–14 days)
    20 May 2016
    • The list of AEs related to ALK inhibitors and alectinib data had been updated to align with the Investigator’s Brochure, Version 6, and the addendum to the Investigator’s Brochure, Version 6. The guideline for management of specific AEs with alectinib had been amended accordingly • Restriction related to concomitant medications known to prolong the QT interval was removed. The restriction was no longer required for alectinib-treated subjects based on the detailed evaluation of the pooled ECG data from the two pivotal studies NCT01871805 and NCT01801111, and ECG data from the supportive AF-001JP study, which showed no evidence of alectinib causing any clinically relevant QTcF prolongation. Further, there was no apparent correlation between the change in QTcF and alectinib plasma concentration. For docetaxel and pemetrexed, no such restrictions were required according to the corresponding labels
    07 Dec 2016
    • Sample size assumptions. The expected median time to PFS was increased from 6 months to 7 months on the alectinib arm (no change in the chemotherapy arm). This change was made because Phase II studies of alectinib in the crizotinib-failure setting had shown a consistent PFS outcome of 8.2–8.9 months, making the original 6-month assumption unrealistic. Consequently, assuming an accrual period of 12 months and a primary analysis with 50 PFS events planned after approximately 13 months, a sample size of 90 subjects (60 subjects in the experimental arm [alectinib] and 30 subjects in the control arm [chemotherapy]) provided 80% power to detect a significant improvement in the median time to PFS from 3 to 7 months (i.e., Hazard ratio [HR] of 0.43). With this new information on efficacy from Phase II studies and the resulting amendment of the NCT02604342 study, the same objective of superiority would be reached, with a smaller sample size and smaller target number of PFS events • Recruitment caps. Earlier versions of the NCT02604342 study protocol had a recruitment cap on the chemotherapy arm, such that 50% of subjects were to receive docetaxel and 50% were to receive pemetrexed. The current version of the protocol removed this constraint. This change was made because current standard of- care therapy in Europe in the front-line setting is a pemetrexed-based chemotherapy. Consequently, few subjects were available for enrollment who had not yet received pemetrexed, presenting a significant recruitment challenge. The change had the additional benefit of making the control arm in the study (chemotherapy) more directly analogous to a standard clinical population
    07 Dec 2016
    • ALK testing. The current version of the protocol no longer specified the exact type and catalog number of the fluorescence in situ hybridization (FISH) test or immunohistochemistry (IHC) test mandated for identification and inclusion of ALK-positive subjects. Instead, the acceptable tests were broadened to include any assays that were validated and in line with published national or international guidelines. This change was made because ALK testing is a routine test performed for selecting subjects eligible for crizotinib
    01 Dec 2017
    Reduction in the number of assessments and subject visits during follow-up due to the study having met its primary objective and because of a favorable safety profile; removal of the mandate for ongoing IRC review; post-treatment visit was changed from 3 months after the last administration of study drug to 4 weeks after the last administration in order to align more closely to other alectinib trials.

    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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