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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 ado-trastuzumab emtansine (T-DM1) for HER2-positive, unresectable and/or metastatic breast cancer subjects previously treated with trastuzumab and taxane

    Summary
    EudraCT number
    2018-000222-61
    Trial protocol
    GB   BE   FR   ES   DE   IT  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Jun 2022
    First version publication date
    09 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DS8201-A-U302
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03529110
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo Inc.
    Sponsor organisation address
    211 Mt. Airy Rd., Basking Ridge, United States, 07920
    Public contact
    Global Clinical Director, Daiichi Sankyo Inc., 908 992-6400, CTRinfo@dsi.com
    Scientific contact
    Global Clinical Director, Daiichi Sankyo Inc., 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
    21 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 May 2021
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of DS 8201a to T-DM1 as measured by progression-free survival (PFS).
    Protection of trial subjects
    The study protocol, amendments, the informed consent form(s) (ICF[s]), and information sheets were approved by the appropriate and applicable Independent Ethics Committees (IECs) or Institutional Review Boards (IRBs). The 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).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Aug 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 38
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Brazil: 63
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    China: 65
    Country: Number of subjects enrolled
    Hong Kong: 21
    Country: Number of subjects enrolled
    Japan: 68
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 84
    Country: Number of subjects enrolled
    Taiwan: 71
    Country: Number of subjects enrolled
    United States: 32
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    United Kingdom: 11
    Worldwide total number of subjects
    524
    EEA total number of subjects
    93
    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)
    418
    From 65 to 84 years
    106
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 524 participants were enrolled & treated at study sites in 14 countries. Primary results reported is from first participant randomized up to data cutoff date of 21 May 2021. The results presented are based on primary analysis up to 33 months. Data collection is still on-going & additional results will be provided after study completion.

    Pre-assignment
    Screening details
    A total of 699 participants were screened and 524 participants enrolled.

    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 trastuzumab and taxane 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, DS-8201a, Enhertu®
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    T-DXd is sterile lyophilized powder reconstituted into a sterile aqueous solution (100 mg/5 mL) to be administered intravenously.

    Arm title
    Ado-trastuzumab Emtansine (T-DM1)
    Arm description
    Participants with HER2-positive, unresectable and/or metastatic breast cancer participants previously treated with trastuzumab and taxane who received T-DM1 in accordance with the approved label.
    Arm type
    Experimental

    Investigational medicinal product name
    ado-trastuzumab emtansine
    Investigational medicinal product code
    Other name
    T-DM1, KADCYLA®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The treatment will be in accordance with the approved label.

    Number of subjects in period 1
    Trastuzumab Deruxtecan (T-DXd) Ado-trastuzumab Emtansine (T-DM1)
    Started
    261
    263
    Completed
    136
    49
    Not completed
    125
    214
         Clinical progression
    4
    12
         Physician decision
    2
    8
         Miscellaneous
    2
    5
         Adverse event
    35
    17
         Progressive disease
    66
    158
         Withdrawal by subject
    13
    11
         Lack of efficacy
    3
    3

    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 trastuzumab and taxane 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
    Ado-trastuzumab Emtansine (T-DM1)
    Reporting group description
    Participants with HER2-positive, unresectable and/or metastatic breast cancer participants previously treated with trastuzumab and taxane who received T-DM1 in accordance with the approved label.

    Reporting group values
    Trastuzumab Deruxtecan (T-DXd) Ado-trastuzumab Emtansine (T-DM1) Total
    Number of subjects
    261 263 524
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    212 206 418
        From 65-84 years
    41 49 90
        85 years and over
    8 8 16
    Age continuous
    Units: years
        median (standard deviation)
    54.5 ± 11.11 54.2 ± 11.84 -
    Gender categorical
    Units: Subjects
        Female
    260 262 522
        Male
    1 1 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    152 162 314
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    10 9 19
        White
    71 72 143
        More than one race
    2 0 2
        Unknown or Not Reported
    26 20 46

    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 trastuzumab and taxane 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
    Ado-trastuzumab Emtansine (T-DM1)
    Reporting group description
    Participants with HER2-positive, unresectable and/or metastatic breast cancer participants previously treated with trastuzumab and taxane who received T-DM1 in accordance with the approved label.

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

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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 Previously Treated With Trastuzumab and Taxane [1]
    End point description
    Progression-free survival (PFS) by BICR was defined as the time from the date of enrollment 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. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. Progression-free survival (PFS) was assessed in the Full Analysis Set at data cut-off date of 21 May 2021.
    End point type
    Primary
    End point timeframe
    Up to 33 months (data cut-off)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed.
    End point values
    Trastuzumab Deruxtecan (T-DXd) Ado-trastuzumab Emtansine (T-DM1)
    Number of subjects analysed
    261 [2]
    263
    Units: months
        median (confidence interval 95%)
    99.9 (18.5 to 99.9)
    6.8 (5.6 to 8.2)
    Notes
    [2] - 99.9=NA, Median and upper CI was not estimable due to insufficient number of events.
    No statistical analyses for this end point

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

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    End point title
    Overall Survival (OS) in Participants With HER2-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane
    End point description
    Overall survival (OS) was defined as the time from the date of first dose of study drug to the date of death due to any cause. Overall survival (OS) was assessed in the Full Analysis Set at data cut-off date of 21 May 2021.
    End point type
    Secondary
    End point timeframe
    Up to 33 months (data cut-off)
    End point values
    Trastuzumab Deruxtecan (T-DXd) Ado-trastuzumab Emtansine (T-DM1)
    Number of subjects analysed
    261 [3]
    263 [4]
    Units: months
        median (confidence interval 95%)
    99.9 (99.9 to 99.9)
    99.9 (99.9 to 99.9)
    Notes
    [3] - 99.9=NA, Median and 95% CI was not estimable due to insufficient number of events.
    [4] - 99.9=NA, Median and 95% CI was not estimable due to insufficient number of events.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Objective Response Rate (ORR) Based on BICR and Investigator Assessment in Participants With HER2-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane

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    End point title
    Percentage of Participants With Objective Response Rate (ORR) Based on BICR and Investigator Assessment in Participants With HER2-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane
    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 is reported. Objective response rate was assessed in the Full Analysis Set at data cut-off date of 21 May 2021.
    End point type
    Secondary
    End point timeframe
    Up to 33 months (data cut-off)
    End point values
    Trastuzumab Deruxtecan (T-DXd) Ado-trastuzumab Emtansine (T-DM1)
    Number of subjects analysed
    261
    263
    Units: Percentage of Participants
    number (confidence interval 95%)
        BICR
    79.7 (74.3 to 84.4)
    34.2 (28.5 to 40.3)
        Investigator Assessment
    77.0 (71.2 to 82.0)
    36.9 (31.0 to 43.0)
    No statistical analyses for this end point

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

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    End point title
    Duration of Response (DoR) Based on BICR and Investigator Assessment in Participants With HER2-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane
    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. Duration of Response (DoR) was assessed in the Full Analysis Set of participants with confirmed CR/PR at data cut-off date of 21 May 2021.
    End point type
    Secondary
    End point timeframe
    Up to 33 months (data cut-off)
    End point values
    Trastuzumab Deruxtecan (T-DXd) Ado-trastuzumab Emtansine (T-DM1)
    Number of subjects analysed
    261 [5]
    263 [6]
    Units: months
    median (confidence interval 95%)
        BICR
    99.9 (20.3 to 99.9)
    99.9 (12.6 to 99.9)
        Investigator Assessment
    99.9 (20.8 to 99.9)
    99.9 (14.1 to 99.9)
    Notes
    [5] - 99.9=NA, Median and upper CI was not estimable due to insufficient number of events.
    [6] - 99.9=NA, Median and 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 Previously Treated With Trastuzumab and Taxane

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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 Previously Treated With Trastuzumab and Taxane
    End point description
    Progression-free survival (PFS) by investigator assessment was defined as the time from the date of enrollment 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. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. Progression-free survival (PFS) was assessed in the Full Analysis Set at data cut-off date of 21 May 2021.
    End point type
    Secondary
    End point timeframe
    Up to 33 months (data cut-off)
    End point values
    Trastuzumab Deruxtecan (T-DXd) Ado-trastuzumab Emtansine (T-DM1)
    Number of subjects analysed
    261 [7]
    263
    Units: months
        median (confidence interval 95%)
    25.1 (22.1 to 99.9)
    7.2 (6.8 to 8.3)
    Notes
    [7] - 99.9=NA, Upper CI was not estimable due to insufficient number of events.
    No statistical analyses for this end point

    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 33 months.
    Adverse event reporting additional description
    A Treatment-emergent adverse event (TEAE) is defined as an AE that occurs, having been absent before the first dose of study drug, or has worsened in severity or seriousness after the initiating the study drug until 47 days after last dose of the study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23
    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 trastuzumab and taxane 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
    Ado-trastuzumab Emtansine (T-DM1)
    Reporting group description
    Participants with HER2-positive, unresectable and/or metastatic breast cancer participants previously treated with trastuzumab and taxane who received T-DM1 in accordance with the approved label.

    Serious adverse events
    Trastuzumab Deruxtecan (T-DXd) Ado-trastuzumab Emtansine (T-DM1)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 257 (19.07%)
    47 / 261 (18.01%)
         number of deaths (all causes)
    33
    53
         number of deaths resulting from adverse events
    5
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angiodysplasia
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial haemorrhage
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Seizure
         subjects affected / exposed
    2 / 257 (0.78%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 257 (1.56%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Disease progression
         subjects affected / exposed
    3 / 257 (1.17%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    5 / 257 (1.95%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal cyst
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 257 (0.00%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biopsy lymph gland
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation necrosis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain herniation
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         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
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasogenic cerebral oedema
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         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 / 257 (0.78%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 257 (0.78%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Otolithiasis
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Rhegmatogenous retinal detachment
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    5 / 257 (1.95%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 257 (0.78%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 257 (0.39%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 257 (0.39%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal polyp haemorrhage
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice cholestatic
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic atrophy
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic failure
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone lesion
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 257 (1.56%)
    5 / 261 (1.92%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 257 (1.17%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 257 (0.78%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 257 (0.39%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Breast cellulitis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    2 / 257 (0.78%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 257 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Trastuzumab Deruxtecan (T-DXd) Ado-trastuzumab Emtansine (T-DM1)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    256 / 257 (99.61%)
    249 / 261 (95.40%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    75 / 257 (29.18%)
    25 / 261 (9.58%)
         occurrences all number
    75
    25
    Aspartate aminotransferase increased
         subjects affected / exposed
    66 / 257 (25.68%)
    105 / 261 (40.23%)
         occurrences all number
    66
    105
    White blood cell count decreased
         subjects affected / exposed
    58 / 257 (22.57%)
    14 / 261 (5.36%)
         occurrences all number
    58
    14
    Alanine aminotransferase increased
         subjects affected / exposed
    56 / 257 (21.79%)
    77 / 261 (29.50%)
         occurrences all number
    56
    77
    Platelet count decreased
         subjects affected / exposed
    54 / 257 (21.01%)
    112 / 261 (42.91%)
         occurrences all number
    54
    112
    Blood alkaline phosphatase increased
         subjects affected / exposed
    35 / 257 (13.62%)
    30 / 261 (11.49%)
         occurrences all number
    35
    30
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    17 / 257 (6.61%)
    35 / 261 (13.41%)
         occurrences all number
    17
    35
    Blood bilirubin increased
         subjects affected / exposed
    17 / 257 (6.61%)
    13 / 261 (4.98%)
         occurrences all number
    17
    13
    Lymphocyte count decreased
         subjects affected / exposed
    14 / 257 (5.45%)
    3 / 261 (1.15%)
         occurrences all number
    14
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    14 / 257 (5.45%)
    6 / 261 (2.30%)
         occurrences all number
    14
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    54 / 257 (21.01%)
    38 / 261 (14.56%)
         occurrences all number
    54
    38
    Dizziness
         subjects affected / exposed
    32 / 257 (12.45%)
    22 / 261 (8.43%)
         occurrences all number
    32
    22
    Peripheral sensory neuropathy
         subjects affected / exposed
    19 / 257 (7.39%)
    25 / 261 (9.58%)
         occurrences all number
    19
    25
    Dysgeusia
         subjects affected / exposed
    15 / 257 (5.84%)
    8 / 261 (3.07%)
         occurrences all number
    15
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    83 / 257 (32.30%)
    43 / 261 (16.48%)
         occurrences all number
    83
    43
    Neutropenia
         subjects affected / exposed
    41 / 257 (15.95%)
    7 / 261 (2.68%)
         occurrences all number
    41
    7
    Leukopenia
         subjects affected / exposed
    22 / 257 (8.56%)
    8 / 261 (3.07%)
         occurrences all number
    22
    8
    Lymphopenia
         subjects affected / exposed
    15 / 257 (5.84%)
    6 / 261 (2.30%)
         occurrences all number
    15
    6
    Thrombocytopenia
         subjects affected / exposed
    13 / 257 (5.06%)
    31 / 261 (11.88%)
         occurrences all number
    13
    31
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    74 / 257 (28.79%)
    52 / 261 (19.92%)
         occurrences all number
    74
    52
    Asthenia
         subjects affected / exposed
    32 / 257 (12.45%)
    31 / 261 (11.88%)
         occurrences all number
    32
    31
    Malaise
         subjects affected / exposed
    29 / 257 (11.28%)
    10 / 261 (3.83%)
         occurrences all number
    29
    10
    Pyrexia
         subjects affected / exposed
    27 / 257 (10.51%)
    39 / 261 (14.94%)
         occurrences all number
    27
    39
    Oedema peripheral
         subjects affected / exposed
    17 / 257 (6.61%)
    9 / 261 (3.45%)
         occurrences all number
    17
    9
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    195 / 257 (75.88%)
    79 / 261 (30.27%)
         occurrences all number
    195
    79
    Vomiting
         subjects affected / exposed
    126 / 257 (49.03%)
    26 / 261 (9.96%)
         occurrences all number
    126
    26
    Constipation
         subjects affected / exposed
    88 / 257 (34.24%)
    51 / 261 (19.54%)
         occurrences all number
    88
    51
    Diarrhoea
         subjects affected / exposed
    75 / 257 (29.18%)
    18 / 261 (6.90%)
         occurrences all number
    75
    18
    Dyspepsia
         subjects affected / exposed
    29 / 257 (11.28%)
    16 / 261 (6.13%)
         occurrences all number
    29
    16
    Abdominal pain
         subjects affected / exposed
    29 / 257 (11.28%)
    5 / 261 (1.92%)
         occurrences all number
    29
    5
    Abdominal pain upper
         subjects affected / exposed
    28 / 257 (10.89%)
    12 / 261 (4.60%)
         occurrences all number
    28
    12
    Gastrooesophageal reflux disease
         subjects affected / exposed
    13 / 257 (5.06%)
    4 / 261 (1.53%)
         occurrences all number
    13
    4
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    29 / 257 (11.28%)
    42 / 261 (16.09%)
         occurrences all number
    29
    42
    Cough
         subjects affected / exposed
    27 / 257 (10.51%)
    26 / 261 (9.96%)
         occurrences all number
    27
    26
    Dyspnoea
         subjects affected / exposed
    21 / 257 (8.17%)
    13 / 261 (4.98%)
         occurrences all number
    21
    13
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 257 (7.78%)
    15 / 261 (5.75%)
         occurrences all number
    20
    15
    Oropharyngeal pain
         subjects affected / exposed
    13 / 257 (5.06%)
    6 / 261 (2.30%)
         occurrences all number
    13
    6
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    95 / 257 (36.96%)
    8 / 261 (3.07%)
         occurrences all number
    95
    8
    Pruritus
         subjects affected / exposed
    21 / 257 (8.17%)
    18 / 261 (6.90%)
         occurrences all number
    21
    18
    Rash
         subjects affected / exposed
    16 / 257 (6.23%)
    24 / 261 (9.20%)
         occurrences all number
    16
    24
    Dry skin
         subjects affected / exposed
    14 / 257 (5.45%)
    4 / 261 (1.53%)
         occurrences all number
    14
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    18 / 257 (7.00%)
    6 / 261 (2.30%)
         occurrences all number
    18
    6
    Insomnia
         subjects affected / exposed
    15 / 257 (5.84%)
    24 / 261 (9.20%)
         occurrences all number
    15
    24
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    24 / 257 (9.34%)
    16 / 261 (6.13%)
         occurrences all number
    24
    16
    Myalgia
         subjects affected / exposed
    23 / 257 (8.95%)
    16 / 261 (6.13%)
         occurrences all number
    23
    16
    Arthralgia
         subjects affected / exposed
    22 / 257 (8.56%)
    23 / 261 (8.81%)
         occurrences all number
    22
    23
    Pain in extremity
         subjects affected / exposed
    21 / 257 (8.17%)
    16 / 261 (6.13%)
         occurrences all number
    21
    16
    Musculoskeletal pain
         subjects affected / exposed
    17 / 257 (6.61%)
    12 / 261 (4.60%)
         occurrences all number
    17
    12
    Infections and infestations
    Stomatitis
         subjects affected / exposed
    40 / 257 (15.56%)
    10 / 261 (3.83%)
         occurrences all number
    40
    10
    Urinary tract infection
         subjects affected / exposed
    19 / 257 (7.39%)
    13 / 261 (4.98%)
         occurrences all number
    19
    13
    Pneumonia
         subjects affected / exposed
    18 / 257 (7.00%)
    9 / 261 (3.45%)
         occurrences all number
    18
    9
    Pneumonitis
         subjects affected / exposed
    18 / 257 (7.00%)
    1 / 261 (0.38%)
         occurrences all number
    18
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    75 / 257 (29.18%)
    44 / 261 (16.86%)
         occurrences all number
    75
    44
    Weight decreased
         subjects affected / exposed
    43 / 257 (16.73%)
    16 / 261 (6.13%)
         occurrences all number
    43
    16
    Hypokalaemia
         subjects affected / exposed
    33 / 257 (12.84%)
    26 / 261 (9.96%)
         occurrences all number
    33
    26
    Hypoalbuminaemia
         subjects affected / exposed
    20 / 257 (7.78%)
    12 / 261 (4.60%)
         occurrences all number
    20
    12

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jun 2018
    Clarified TEAEs section. Updated dose information & modification section and inclusion & exclusion criteria section. Updated definitions of Grade 2, 3, and 4 for specific investigations. Clarified language for timing of signed and dated written consent. Clarified details of urine pregnancy test results. Clarified details of lab procedures. Added details for PK sampling.
    08 Mar 2019
    Clarified the primary objective and updated secondary endpoints. Updated inclusion and exclusion criteria. Updated and clarified AE reporting and follow-up. Updated dose modification, screening, and lab sections. Updated PK sampling times. Updated procedures section.
    26 Apr 2019
    Clarified interstitial lung disease information.
    23 Apr 2020
    Added additional analyses of PFS and OS. Updated the secondary endpoint of OS. Updated the exploratory endpoints. Updated inclusion & exclusion criteria section. Updated general statistical considerations and dose modification sections. Updated screening and lab procedures. Clarified the PK sampling and end of treatment timing. Updated AE of Special Interest. Updated the Schedule of Events section.
    25 Sep 2020
    Updated to incorporate the COVID-19 management procedures. Updated exploratory endpoints to include PFS on next line therapy. Clarified withdrawal of consent language.

    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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