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    Clinical Trial Results:
    A Phase 3, multicenter, randomized, open-label, active-controlled study of DS-8201a, an anti-HER2-antibody drug conjugate, versus treatment of investigator’s choice for HER2-positive, unresectable and/or metastatic breast cancer subjects pretreated with prior standard of care HER2 therapies, including T-DM1

    Summary
    EudraCT number
    		 2018-000221-31
    Trial protocol
    		 GB   BE   CZ   FR   GR   DE   IT   ES  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Sep 2023
    First version publication date
    30 Sep 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DS8201-A-U301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03523585
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo
    Sponsor organisation address
    211 Mount Airy Rd, Basking Ridge, United States, 07920
    Public contact
    Contact for Clinical Trial Information, Daiichi Sankyo Inc., +1 908 992 6400, CTRinfo@dsi.com
    Scientific contact
    Contact for Clinical Trial Information, Daiichi Sankyo Inc., +1 908 992 6400, CTRinfo@dsi.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
    30 Jun 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2022
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    • To compare the progression-free survival (PFS) benefit of DS-8201a to investigator’s choice.
    Protection of trial subjects
    This study was conducted in compliance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Council for Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and applicable regulatory requirement(s). The study protocol, amendments, the informed consent forms (ICF), and information sheets were approved by the appropriate and applicable Independent Ethics Committees (IECs) or Institutional Review Boards (IRBs).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 35
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    France: 57
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Greece: 14
    Country: Number of subjects enrolled
    Italy: 53
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Brazil: 59
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Japan: 70
    Country: Number of subjects enrolled
    Korea, Republic of: 94
    Country: Number of subjects enrolled
    Spain: 44
    Country: Number of subjects enrolled
    Turkey: 52
    Country: Number of subjects enrolled
    United States: 64
    Worldwide total number of subjects
    608
    EEA total number of subjects
    230
    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)
    485
    From 65 to 84 years
    119
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 608 participants were enrolled at study sites in 15 countries. Primary results reported is from first participant randomized up to data cut-off date of 30 Jun 2022. The results presented are based on primary analysis up to 46 months.

    Pre-assignment
    Screening details
    		 Participants in The Physician's Choice (TPC) group were randomized to either trastuzumab/capecitabine or lapatinib/capecitabine. As prespecified, participants were assessed and reported separately per arm for the disposition, baseline characteristics, and safety tables. For efficacy assessments, all TPC participants were assessed together.

    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
    		 Trastuzumab Deruxtecan (T-DXd)
    Arm description
    		 Participants with HER2 positive, unresectable and/or metastatic breast cancer participants previously treated with standard of care HER2 therapies, including ado-trastuzumab emtansine (T-DM1), who received T-DXd as a sterile intravenous (IV) solution at a dose of 5.4 mg/kg every 3 weeks (Q3W).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab Deruxtecan
    Investigational medicinal product code
    Other name
    T-DXd
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    T-DXd for injection, 100 mg, was administered intravenously (IV) at a starting dose of 5.4 mg/kg every 3 weeks (Q3W).

    Arm title
    		 Trastuzumab+Capecitabine
    Arm description
    		 Participants with HER2 positive, unresectable and/or metastatic breast cancer participants previously treated with standard of care HER2 therapies, including ado-trastuzumab emtansine (T-DM1), who received investigator's choice treatment, Trastuzumab/Capecitabine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Capecitabine 1250 mg/m2 administered orally (PO) twice daily approximately 12 hours apart (equivalent to 2500 mg/m2 total daily dose) on Days 1 to 14 of a 21-day (± 2 days) schedule

    Investigational medicinal product name
    Trastuzumab Deruxtecan
    Investigational medicinal product code
    Other name
    T-DXd
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    T-DXd for injection, 100 mg, was administered intravenously (IV) at a starting dose of 5.4 mg/kg every 3 weeks (Q3W).

    Arm title
    		 Lapatinib+Capecitabine
    Arm description
    		 Participants with HER2 positive, unresectable and/or metastatic breast cancer participants previously treated with standard of care HER2 therapies, including ado-trastuzumab emtansine (T-DM1), who received investigator's choice treatment, Lapatinib/Capecitabine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Lapatinib 1250 mg PO daily on Days 1 to 21 of a 21-day (± 2 days) schedule

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Capecitabine 1250 mg/m2 administered orally (PO) twice daily approximately 12 hours apart (equivalent to 2500 mg/m2 total daily dose) on Days 1 to 14 of a 21-day (± 2 days) schedule

    Number of subjects in period 1
    		Trastuzumab Deruxtecan (T-DXd) Trastuzumab+Capecitabine Lapatinib+Capecitabine
    Started
    406
    91
    111
    Completed
    94
    1
    4
    Not completed
    312
    90
    107
         Clinical progression
    23
    5
    10
         Physician decision
    2
    1
    -
         Adverse event, non-fatal
    74
    5
    9
         Randomized but not treated
    2
    4
    3
         Death
    4
    -
    1
         Miscellaneous
    1
    -
    -
         Lost to follow-up
    1
    -
    -
         Progressive disease
    174
    64
    77
         Protocol deviation
    1
    -
    1
         Withdrawal by subject
    30
    11
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trastuzumab Deruxtecan (T-DXd)
    Reporting group description
    		 Participants with HER2 positive, unresectable and/or metastatic breast cancer participants previously treated with standard of care HER2 therapies, including ado-trastuzumab emtansine (T-DM1), who received T-DXd as a sterile intravenous (IV) solution at a dose of 5.4 mg/kg every 3 weeks (Q3W).

    Reporting group title
    Trastuzumab+Capecitabine
    Reporting group description
    		 Participants with HER2 positive, unresectable and/or metastatic breast cancer participants previously treated with standard of care HER2 therapies, including ado-trastuzumab emtansine (T-DM1), who received investigator's choice treatment, Trastuzumab/Capecitabine.

    Reporting group title
    Lapatinib+Capecitabine
    Reporting group description
    		 Participants with HER2 positive, unresectable and/or metastatic breast cancer participants previously treated with standard of care HER2 therapies, including ado-trastuzumab emtansine (T-DM1), who received investigator's choice treatment, Lapatinib/Capecitabine.

    Reporting group values
    		 Trastuzumab Deruxtecan (T-DXd) Trastuzumab+Capecitabine Lapatinib+Capecitabine Total
    Number of subjects
    		 406 91 111 608
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 321 73 91 485
        From 65-84 years
    		 82 17 20 119
        85 years and over
    		 3 1 0 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.6 ± 11.99 55.7 ± 11.40 54.6 ± 11.06 -
    Gender categorical
    Units: Subjects
        Female
    		 403 89 111 603
        Male
    		 3 2 0 5

    End points

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    End points reporting groups
    Reporting group title
    Trastuzumab Deruxtecan (T-DXd)
    Reporting group description
    		 Participants with HER2 positive, unresectable and/or metastatic breast cancer participants previously treated with standard of care HER2 therapies, including ado-trastuzumab emtansine (T-DM1), who received T-DXd as a sterile intravenous (IV) solution at a dose of 5.4 mg/kg every 3 weeks (Q3W).

    Reporting group title
    Trastuzumab+Capecitabine
    Reporting group description
    		 Participants with HER2 positive, unresectable and/or metastatic breast cancer participants previously treated with standard of care HER2 therapies, including ado-trastuzumab emtansine (T-DM1), who received investigator's choice treatment, Trastuzumab/Capecitabine.

    Reporting group title
    Lapatinib+Capecitabine
    Reporting group description
    		 Participants with HER2 positive, unresectable and/or metastatic breast cancer participants previously treated with standard of care HER2 therapies, including ado-trastuzumab emtansine (T-DM1), who received investigator's choice treatment, Lapatinib/Capecitabine.

    Subject analysis set title
    The Physician's Choice (TPC)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patient's in Th Physician's Choice group were randomized to 1 of the following 2 regimens: trastuzumab/capecitabine or lapatinib/capecitabine.

    Primary: Progression-Free Survival (PFS) Based on Blinded Independent Central Review (BICR) in Participants With HER2- positive, Unresectable and/or Metastatic Breast Cancer Participants Previously Treated With Trastuzumab Emtansine

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    End point title
    		 Progression-Free Survival (PFS) Based on Blinded Independent Central Review (BICR) in Participants With HER2- positive, Unresectable and/or Metastatic Breast Cancer Participants Previously Treated With Trastuzumab Emtansine [1]
    End point description
    Progression-free survival (PFS) by BICR was defined as the time from the date of randomization to the earlier of the dates of the first objective documentation of disease progression (as per RECIST v1.1) or death due to any cause.
    End point type
    Primary
    End point timeframe
    Baseline up to 46 months postdose
    Notes
    [1] - 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: As prespecified in the protocol, participants were assessed and reported separately per comparator arm for the disposition, baseline characteristics, and safety tables. For efficacy assessments, all participants in the TPC group were combined and assessed together.
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) The Physician's Choice (TPC)
    Number of subjects analysed
    406
    202
    Units: months
    median (confidence interval 95%)
        Progression-free survival (PFS)
    17.8 (14.3 to 20.8)
    6.9 (5.5 to 8.4)
    Statistical analysis title
    		 T-DXd vs TPC
    Comparison groups
    Trastuzumab Deruxtecan (T-DXd) v The Physician's Choice (TPC)
    Number of subjects included in analysis
    608
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.000001 [2]
    Method
    		 Stratified log rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.3589
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.284
         upper limit
    		 0.4535
    Notes
    [2] - p value based on log-rank stratified by hormone receptor status, prior treatment with pertuzumab, and history of visceral disease, as defined by IXRS

    Secondary: Overall Survival (OS) in Participants With HER2-positive, Unresectable and/or Metastatic Breast Cancer Participants Previously Treated With Trastuzumab Emtansine

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    End point title
    		 Overall Survival (OS) in Participants With HER2-positive, Unresectable and/or Metastatic Breast Cancer Participants Previously Treated With Trastuzumab Emtansine [3]
    End point description
    Overall survival (OS) was defined as the time from the date of randomization to the date of death due to any cause. If there is no death reported for a subject before the data cutoff for OS analysis, OS will be censored at the last contact date at which the subject is known to be alive.
    End point type
    Secondary
    End point timeframe
    Baseline up to 46 months postdose
    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: As prespecified in the protocol, participants were assessed and reported separately per comparator arm for the disposition, baseline characteristics, and safety tables. For efficacy assessments, all participants in the TPC group were combined and assessed together.
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) The Physician's Choice (TPC)
    Number of subjects analysed
    406 [4]
    202 [5]
    Units: months
    median (confidence interval 95%)
        Overall survival (OS)
    39.2 (32.7 to 9999)
    26.5 (21.0 to 9999)
    Notes
    [4] - 9999=Upper limit of 95% CI was not estimable due to insufficient number of events
    [5] - 9999=Upper limit of 95% CI was not estimable due to insufficient number of events
    Statistical analysis title
    		 T-DXd vs TPC
    Comparison groups
    Trastuzumab Deruxtecan (T-DXd) v The Physician's Choice (TPC)
    Number of subjects included in analysis
    608
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0021 [6]
    Method
    		 Stratified log rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6575
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5023
         upper limit
    		 0.8605
    Notes
    [6] - p value based on log-rank stratified by hormone receptor status, prior treatment with pertuzumab, and history of visceral disease, as defined by IXRS

    Secondary: Percentage of Patients With Objective Response Rate (ORR) in Participants With HER2-positive, Unresectable and/ or Metastatic Breast Cancer Participants Previously Treated With Trastuzumab Emtansine

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    End point title
    		 Percentage of Patients With Objective Response Rate (ORR) in Participants With HER2-positive, Unresectable and/ or Metastatic Breast Cancer Participants Previously Treated With Trastuzumab Emtansine [7]
    End point description
    The Objective Response Rate (ORR) was defined as the percentage of participants who achieved a best overall response of confirmed Complete Response (CR) or Partial Response (PR), assessed by BICR and investigator assessment based on RECIST version 1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. Confirmed ORR based on BICR and Investigator Assessment is reported.
    End point type
    Secondary
    End point timeframe
    Baseline up to 46 months postdose
    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: As prespecified in the protocol, participants were assessed and reported separately per comparator arm for the disposition, baseline characteristics, and safety tables. For efficacy assessments, all participants in the TPC group were combined and assessed together.
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) The Physician's Choice (TPC)
    Number of subjects analysed
    406
    202
    Units: percentage of patients
    number (confidence interval 95%)
        BICR
    69.7 (65.0 to 74.1)
    29.2 (23.0 to 36.0)
        Investigator Assessment
    74.1 (69.6 to 78.3)
    26.7 (20.8 to 33.4)
    Statistical analysis title
    		 T-DXd vs TPC; BICR
    Comparison groups
    Trastuzumab Deruxtecan (T-DXd) v The Physician's Choice (TPC)
    Number of subjects included in analysis
    608
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [8] - Cochran-Mantel-Haenszel test adjusted for stratification factors: hormone receptor status, prior treatment with pertuzumab, and history of visceral disease, as defined by the IXRS.
    Statistical analysis title
    		 T-DXd vs TPC; Investigator Assessment
    Comparison groups
    Trastuzumab Deruxtecan (T-DXd) v The Physician's Choice (TPC)
    Number of subjects included in analysis
    608
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [9] - Cochran-Mantel-Haenszel test adjusted for stratification factors: hormone receptor status, prior treatment with pertuzumab, and history of visceral disease, as defined by the IXRS.

    Secondary: Duration of Response (DoR) Based on BICR in Participants With HER2-positive, Unresectable and/or Metastatic Breast Cancer Participants Previously Treated With Trastuzumab Emtansine

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    End point title
    		 Duration of Response (DoR) Based on BICR in Participants With HER2-positive, Unresectable and/or Metastatic Breast Cancer Participants Previously Treated With Trastuzumab Emtansine [10]
    End point description
    Duration of Response (DoR) was defined as the time from the date of the first documentation of objective response (complete response [CR] or partial response [PR]) to the date of the first objective documentation of progressive disease (PD) or death due to any cause. DoR in participants with confirmed CR/PR based on BICR and investigator assessment is reported.
    End point type
    Secondary
    End point timeframe
    Baseline up to 46 months postdose
    Notes
    [10] - 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: As prespecified in the protocol, participants were assessed and reported separately per comparator arm for the disposition, baseline characteristics, and safety tables. For efficacy assessments, all participants in the TPC group were combined and assessed together.
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) The Physician's Choice (TPC)
    Number of subjects analysed
    283 [11]
    59
    Units: months
    median (confidence interval 95%)
        Duration of response (DoR)
    19.6 (15.9 to 9999)
    8.3 (5.8 to 9.5)
    Notes
    [11] - 9999=Upper CI was not estimable due to insufficient number of events.
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Based on Investigator Assessment in Participants With HER2-positive, Unresectable and/or Metastatic Breast Cancer Participants Previously Treated With Trastuzumab Emtansine

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    End point title
    		 Progression-Free Survival (PFS) Based on Investigator Assessment in Participants With HER2-positive, Unresectable and/or Metastatic Breast Cancer Participants Previously Treated With Trastuzumab Emtansine [12]
    End point description
    Progression-free survival (PFS) by investigator assessment was defined as the time from the date of randomization to the earlier of the dates of the first objective documentation of disease progression (as per RECIST v1.1) or death due to any cause.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    Notes
    [12] - 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: As prespecified in the protocol, participants were assessed and reported separately per comparator arm for the disposition, baseline characteristics, and safety tables. For efficacy assessments, all participants in the TPC group were combined and assessed together.
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) The Physician's Choice (TPC)
    Number of subjects analysed
    406
    202
    Units: months
    median (confidence interval 95%)
        Progression-free survival (PFS); Investigator
    16.7 (14.3 to 19.6)
    5.5 (4.4 to 7.0)
    Statistical analysis title
    		 T-DXd vs TPC; Investigator Assessment
    Comparison groups
    Trastuzumab Deruxtecan (T-DXd) v The Physician's Choice (TPC)
    Number of subjects included in analysis
    608
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.000001 [13]
    Method
    		 Stratified log rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.2828
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.227
         upper limit
    		 0.3524
    Notes
    [13] - p value based on log-rank stratified by hormone receptor status, prior treatment with pertuzumab, and history of visceral disease, as defined by IXRS

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AE) were collected from the date of signing the informed consent form up to 47 days after last dose of the study drug, up 46 months.
    Adverse event reporting additional description
    A TEAE is an AE that occurs, having been absent before the first dose, or has worsened in severity or seriousness after the initiating the study drug until 47 days after last dose. AEs were assessed in the SAS at data cutoff date of 30 Jun 2022. All-Cause Mortality was analyzed in the FAS. Serious and Other AEs were analyzed in the SAS.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Trastuzumab Deruxtecan (T-DXd)
    Reporting group description
    		 Participants with HER2 positive, unresectable and/or metastatic breast cancer participants previously treated with standard of care HER2 therapies, including ado-trastuzumab emtansine (T-DM1), who received T-DXd as a sterile intravenous (IV) solution at a dose of 5.4 mg/kg every 3 weeks (Q3W).

    Reporting group title
    Trastuzumab+Capecitabine
    Reporting group description
    		 Participants with HER2 positive, unresectable and/or metastatic breast cancer participants previously treated with standard of care HER2 therapies, including ado-trastuzumab emtansine (T-DM1), who received investigator's choice treatment, Trastuzumab/Capecitabine.

    Reporting group title
    Lapatinib+Capecitabine
    Reporting group description
    		 Participants with HER2 positive, unresectable and/or metastatic breast cancer participants previously treated with standard of care HER2 therapies, including ado-trastuzumab emtansine (T-DM1), who received investigator's choice treatment, Lapatinib/Capecitabine.

    Serious adverse events
    		 Trastuzumab Deruxtecan (T-DXd) Trastuzumab+Capecitabine Lapatinib+Capecitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    103 / 404 (25.50%)
    19 / 87 (21.84%)
    27 / 108 (25.00%)
         number of deaths (all causes)
    143
    40
    46
         number of deaths resulting from adverse events
    11
    1
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 87 (1.15%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metastases to ovary
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tumour thrombotic microangiopathy
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Brachiocephalic vein thrombosis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 87 (1.15%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 87 (1.15%)
    3 / 108 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    Fatigue
         subjects affected / exposed
    3 / 404 (0.74%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 404 (0.74%)
    1 / 87 (1.15%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 404 (0.74%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal haemorrhage
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 404 (0.50%)
    1 / 87 (1.15%)
    3 / 108 (2.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    10 / 404 (2.48%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    11 / 11
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic enzymes increased
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 87 (1.15%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiation necrosis
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune thyroiditis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopat
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 87 (1.15%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Monoplegia
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasogenic cerebral oedema
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 404 (0.99%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Scleritis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 404 (0.50%)
    3 / 87 (3.45%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 87 (1.15%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 404 (0.74%)
    3 / 87 (3.45%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric antral vascular ectasia
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 404 (1.24%)
    2 / 87 (2.30%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    6 / 404 (1.49%)
    2 / 87 (2.30%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 87 (1.15%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 87 (1.15%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    11 / 404 (2.72%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 87 (1.15%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gingivitis
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 87 (1.15%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 87 (1.15%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 404 (0.00%)
    1 / 87 (1.15%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 404 (1.49%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 404 (0.00%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 87 (1.15%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 404 (0.99%)
    0 / 87 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 404 (0.25%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Trastuzumab Deruxtecan (T-DXd) Trastuzumab+Capecitabine Lapatinib+Capecitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    404 / 404 (100.00%)
    87 / 87 (100.00%)
    108 / 108 (100.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    61 / 404 (15.10%)
    6 / 87 (6.90%)
    14 / 108 (12.96%)
         occurrences all number
    96
    6
    15
    Aspartate aminotransferase increased
         subjects affected / exposed
    66 / 404 (16.34%)
    5 / 87 (5.75%)
    18 / 108 (16.67%)
         occurrences all number
    103
    8
    20
    Blood alkaline phosphatase increased
         subjects affected / exposed
    24 / 404 (5.94%)
    4 / 87 (4.60%)
    4 / 108 (3.70%)
         occurrences all number
    30
    4
    4
    Blood bilirubin increased
         subjects affected / exposed
    20 / 404 (4.95%)
    4 / 87 (4.60%)
    17 / 108 (15.74%)
         occurrences all number
    26
    5
    29
    Lymphocyte count decreased
         subjects affected / exposed
    30 / 404 (7.43%)
    2 / 87 (2.30%)
    2 / 108 (1.85%)
         occurrences all number
    46
    3
    2
    Neutrophil count decreased
         subjects affected / exposed
    79 / 404 (19.55%)
    7 / 87 (8.05%)
    7 / 108 (6.48%)
         occurrences all number
    227
    8
    15
    Platelet count decreased
         subjects affected / exposed
    49 / 404 (12.13%)
    5 / 87 (5.75%)
    7 / 108 (6.48%)
         occurrences all number
    92
    7
    7
    Weight decreased
         subjects affected / exposed
    71 / 404 (17.57%)
    2 / 87 (2.30%)
    5 / 108 (4.63%)
         occurrences all number
    74
    2
    5
    White blood cell count decreased
         subjects affected / exposed
    59 / 404 (14.60%)
    5 / 87 (5.75%)
    4 / 108 (3.70%)
         occurrences all number
    145
    10
    10
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    32 / 404 (7.92%)
    5 / 87 (5.75%)
    9 / 108 (8.33%)
         occurrences all number
    38
    5
    11
    Dysgeusia
         subjects affected / exposed
    33 / 404 (8.17%)
    3 / 87 (3.45%)
    1 / 108 (0.93%)
         occurrences all number
    35
    3
    1
    Headache
         subjects affected / exposed
    79 / 404 (19.55%)
    7 / 87 (8.05%)
    5 / 108 (4.63%)
         occurrences all number
    116
    8
    5
    Neuropathy peripheral
         subjects affected / exposed
    12 / 404 (2.97%)
    6 / 87 (6.90%)
    4 / 108 (3.70%)
         occurrences all number
    15
    6
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    114 / 404 (28.22%)
    13 / 87 (14.94%)
    13 / 108 (12.04%)
         occurrences all number
    203
    15
    14
    Leukopenia
         subjects affected / exposed
    23 / 404 (5.69%)
    2 / 87 (2.30%)
    2 / 108 (1.85%)
         occurrences all number
    41
    2
    2
    Lymphopenia
         subjects affected / exposed
    21 / 404 (5.20%)
    1 / 87 (1.15%)
    1 / 108 (0.93%)
         occurrences all number
    43
    1
    1
    Neutropenia
         subjects affected / exposed
    65 / 404 (16.09%)
    4 / 87 (4.60%)
    6 / 108 (5.56%)
         occurrences all number
    138
    4
    10
    Thrombocytopenia
         subjects affected / exposed
    41 / 404 (10.15%)
    4 / 87 (4.60%)
    7 / 108 (6.48%)
         occurrences all number
    68
    7
    15
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    97 / 404 (24.01%)
    6 / 87 (6.90%)
    13 / 108 (12.04%)
         occurrences all number
    179
    9
    13
    Fatigue
         subjects affected / exposed
    144 / 404 (35.64%)
    20 / 87 (22.99%)
    32 / 108 (29.63%)
         occurrences all number
    223
    23
    40
    Mucosal inflammation
         subjects affected / exposed
    15 / 404 (3.71%)
    6 / 87 (6.90%)
    9 / 108 (8.33%)
         occurrences all number
    22
    7
    10
    Oedema peripheral
         subjects affected / exposed
    27 / 404 (6.68%)
    4 / 87 (4.60%)
    5 / 108 (4.63%)
         occurrences all number
    37
    4
    5
    Pyrexia
         subjects affected / exposed
    51 / 404 (12.62%)
    5 / 87 (5.75%)
    7 / 108 (6.48%)
         occurrences all number
    68
    5
    8
    Eye disorders
    Dry eye
         subjects affected / exposed
    23 / 404 (5.69%)
    4 / 87 (4.60%)
    5 / 108 (4.63%)
         occurrences all number
    24
    4
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    45 / 404 (11.14%)
    7 / 87 (8.05%)
    11 / 108 (10.19%)
         occurrences all number
    63
    9
    13
    Abdominal pain upper
         subjects affected / exposed
    38 / 404 (9.41%)
    7 / 87 (8.05%)
    11 / 108 (10.19%)
         occurrences all number
    82
    7
    14
    Constipation
         subjects affected / exposed
    142 / 404 (35.15%)
    12 / 87 (13.79%)
    9 / 108 (8.33%)
         occurrences all number
    194
    13
    12
    Diarrhoea
         subjects affected / exposed
    109 / 404 (26.98%)
    33 / 87 (37.93%)
    69 / 108 (63.89%)
         occurrences all number
    216
    44
    156
    Dyspepsia
         subjects affected / exposed
    48 / 404 (11.88%)
    6 / 87 (6.90%)
    12 / 108 (11.11%)
         occurrences all number
    62
    6
    12
    Nausea
         subjects affected / exposed
    292 / 404 (72.28%)
    29 / 87 (33.33%)
    44 / 108 (40.74%)
         occurrences all number
    790
    34
    54
    Stomatitis
         subjects affected / exposed
    44 / 404 (10.89%)
    11 / 87 (12.64%)
    25 / 108 (23.15%)
         occurrences all number
    59
    14
    28
    Vomiting
         subjects affected / exposed
    150 / 404 (37.13%)
    9 / 87 (10.34%)
    14 / 108 (12.96%)
         occurrences all number
    335
    12
    22
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    53 / 404 (13.12%)
    7 / 87 (8.05%)
    13 / 108 (12.04%)
         occurrences all number
    67
    8
    14
    Dyspnoea
         subjects affected / exposed
    33 / 404 (8.17%)
    3 / 87 (3.45%)
    10 / 108 (9.26%)
         occurrences all number
    39
    3
    13
    Epistaxis
         subjects affected / exposed
    33 / 404 (8.17%)
    5 / 87 (5.75%)
    7 / 108 (6.48%)
         occurrences all number
    39
    5
    8
    Pneumonitis
         subjects affected / exposed
    25 / 404 (6.19%)
    0 / 87 (0.00%)
    0 / 108 (0.00%)
         occurrences all number
    25
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    150 / 404 (37.13%)
    4 / 87 (4.60%)
    4 / 108 (3.70%)
         occurrences all number
    165
    4
    4
    Dermatitis acneiform
         subjects affected / exposed
    2 / 404 (0.50%)
    0 / 87 (0.00%)
    10 / 108 (9.26%)
         occurrences all number
    2
    0
    15
    Dry skin
         subjects affected / exposed
    11 / 404 (2.72%)
    3 / 87 (3.45%)
    6 / 108 (5.56%)
         occurrences all number
    11
    3
    6
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    7 / 404 (1.73%)
    48 / 87 (55.17%)
    52 / 108 (48.15%)
         occurrences all number
    9
    66
    64
    Pruritus
         subjects affected / exposed
    22 / 404 (5.45%)
    2 / 87 (2.30%)
    6 / 108 (5.56%)
         occurrences all number
    26
    2
    6
    Rash
         subjects affected / exposed
    27 / 404 (6.68%)
    3 / 87 (3.45%)
    19 / 108 (17.59%)
         occurrences all number
    28
    4
    21
    Rash maculo-papular
         subjects affected / exposed
    6 / 404 (1.49%)
    2 / 87 (2.30%)
    6 / 108 (5.56%)
         occurrences all number
    7
    3
    6
    Skin toxicity
         subjects affected / exposed
    1 / 404 (0.25%)
    1 / 87 (1.15%)
    6 / 108 (5.56%)
         occurrences all number
    1
    1
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    25 / 404 (6.19%)
    6 / 87 (6.90%)
    5 / 108 (4.63%)
         occurrences all number
    27
    6
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    42 / 404 (10.40%)
    7 / 87 (8.05%)
    7 / 108 (6.48%)
         occurrences all number
    56
    7
    7
    Back pain
         subjects affected / exposed
    36 / 404 (8.91%)
    1 / 87 (1.15%)
    5 / 108 (4.63%)
         occurrences all number
    38
    1
    5
    Muscle spasms
         subjects affected / exposed
    13 / 404 (3.22%)
    4 / 87 (4.60%)
    7 / 108 (6.48%)
         occurrences all number
    22
    4
    7
    Myalgia
         subjects affected / exposed
    23 / 404 (5.69%)
    4 / 87 (4.60%)
    4 / 108 (3.70%)
         occurrences all number
    37
    4
    4
    Pain in extremity
         subjects affected / exposed
    24 / 404 (5.94%)
    4 / 87 (4.60%)
    4 / 108 (3.70%)
         occurrences all number
    30
    5
    4
    Infections and infestations
    COVID-19
         subjects affected / exposed
    47 / 404 (11.63%)
    1 / 87 (1.15%)
    2 / 108 (1.85%)
         occurrences all number
    52
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    21 / 404 (5.20%)
    3 / 87 (3.45%)
    2 / 108 (1.85%)
         occurrences all number
    25
    3
    2
    Paronychia
         subjects affected / exposed
    10 / 404 (2.48%)
    3 / 87 (3.45%)
    11 / 108 (10.19%)
         occurrences all number
    12
    4
    20
    Upper respiratory tract infection
         subjects affected / exposed
    21 / 404 (5.20%)
    3 / 87 (3.45%)
    3 / 108 (2.78%)
         occurrences all number
    25
    3
    3
    Urinary tract infection
         subjects affected / exposed
    34 / 404 (8.42%)
    3 / 87 (3.45%)
    3 / 108 (2.78%)
         occurrences all number
    58
    3
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    124 / 404 (30.69%)
    15 / 87 (17.24%)
    20 / 108 (18.52%)
         occurrences all number
    171
    16
    25
    Hypokalaemia
         subjects affected / exposed
    28 / 404 (6.93%)
    7 / 87 (8.05%)
    6 / 108 (5.56%)
         occurrences all number
    40
    8
    6

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jun 2018
    Updated the starting dose of T-DXd to 5.4 mg/kg, clarified if study treatment was delayed more than 4 weeks from the planned date of administration, the subject was withdrawn from study drug, removed stipulation that Sponsor was to provide all TPC medication, clarified that if archived tissue was not available, a fresh biopsy was required, and updated inclusion and exclusion criteria
    08 Mar 2019
    Clarified that complete and partial responses included confirmation of response and that the related objectives and endpoints were to use confirmed responses, clarified that for the TPC arm administration, dose adjustments, prohibited medication, and monitoring were to follow the locally approved label, clarified that secondary analyses were to be performed at the time of primary PFS analysis, updated CBR from a secondary objective/endpoint to be an exploratory objective/endpoint, and updated inclusion and exclusion criteria
    26 Apr 2019
    Updated the ILD monitoring plan and ILD dose modification guidelines to clarify that study drug could be interrupted for any ILD event and that subjects with an ILD event of CTCAE Grade 2, 3 or 4 be permanently discontinued from study drug
    23 Apr 2020
    Added an interim analysis that allowed for an earlier evaluation of OS to coincide with the PFS analysis, updated the secondary objective and endpoint of OS to be a key secondary efficacy objective and endpoint, updated the intent-to-treat analysis set to be the FAS, added an appendix with instructions related to COVID-19 including prohibiting the use of chloroquine and hydroxychloroquine during the treatment period and instituting a washout period, clarified that tumor assessments were conducted every 6 weeks from randomization and were performed while the subject remained on study until progression of disease, withdrawal of consent, death, or loss to follow-up, updated inclusion and exclusion criteria, and updated LVEF monitoring and ILD monitoring and management guidelines
    05 Aug 2020
    Added biomarker analyses to evaluate the impact of the global pandemic caused by COVID-19 at the subject-level and study-level, revised exploratory endpoints to include evaluation of PFS2 and added the corresponding analysis as well as clarifying the withdrawal of consent language, and updated inclusion and exclusion criteria
    17 Mar 2022
    Introduced alterative timing for the primary endpoint and an additional time-based condition to conduct the primary analysis was added and defined the end-of-study hypothesis testing period and study closure

    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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