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    Clinical Trial Results:
    A Phase 2, Multicenter, Open-Label, 2-Cohort Study of Trastuzumab Deruxtecan (DS-8201a), an Anti-HER2 Antibody Drug Conjugate (ADC), for HER2-Over-Expressing or -Mutated, Unresectable and/or Metastatic Non Small Cell Lung Cancer (NSCLC)

    Summary
    EudraCT number
    		 2017-004781-94
    Trial protocol
    		 NL   ES  
    Global end of trial date

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

    Trial information

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    Trial identification
    Sponsor protocol code
    DS8201-A-U204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03505710
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo Inc.
    Sponsor organisation address
    211 Mt. Airy Rd., Baking 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
    03 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 May 2021
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the objective response rate (ORR) of trastuzumab deruxtecan in HER2-over-expressing and/or –HER2 mutated advanced NSCLC subjects.
    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
    21 May 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
    United States: 67
    Country: Number of subjects enrolled
    Japan: 38
    Country: Number of subjects enrolled
    Netherlands: 31
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Spain: 27
    Worldwide total number of subjects
    181
    EEA total number of subjects
    76
    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)
    109
    From 65 to 84 years
    70
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Total of 181 participants were enrolled & treated at centers in Japan, US, France, Netherlands, & Spain. Primary results reported is from baseline to data cut-off date of 03 May 2021. The results presented are based on primary analysis up to 36 months. Data collection is still on-going and additional results will be provided after study completion.

    Pre-assignment
    Screening details
    		 Duration of follow-up (months) was defined as ((last visit date − enrollment date + 1)/365.25) × 12. Last visit date was the date of last clinical visit for ongoing participants, date of death for participants who died, or the last known contact date in survival follow-up for other participants who discontinued study drug.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: HER2 Overexpressing
    Arm description
    		 Participants with HER2-overexpressing(immunohistochemistry [IHC] 3+ or IHC 2+), unresectable and/or metastatic NSCLC adenocarcinoma who received 6.4 mg/kg trastuzumab deruxtecan (DS-8201a). Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DS-8201a
    Investigational medicinal product code
    Other name
    Trastuzumab deruxtecan
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.

    Arm title
    		 Cohort 1a: HER2 Overexpressing
    Arm description
    		 Participants with HER2-overexpressing (immunohistochemistry [IHC] 3+ or IHC 2+), unresectable and/or metastatic NSCLC adenocarcinoma who received 5.4 mg/kg trastuzumab deruxtecan (DS-8201a). Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DS-8201a
    Investigational medicinal product code
    Other name
    Trastuzumab deruxtecan
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.

    Arm title
    		 Cohort 2: HER2 Mutated
    Arm description
    		 Participants with HER2-mutated, unresectable and/or metastatic NSCLC who received 6.4 mg/kg trastuzumab deruxtecan (DS-8201a). Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DS-8201a
    Investigational medicinal product code
    Other name
    Trastuzumab deruxtecan
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.

    Number of subjects in period 1
    		Cohort 1: HER2 Overexpressing Cohort 1a: HER2 Overexpressing Cohort 2: HER2 Mutated
    Started
    49
    41
    91
    Completed
    2
    14
    15
    Not completed
    47
    27
    76
         Physician decision
    1
    -
    2
         Adverse Event
    12
    5
    27
         Other Reasons
    1
    1
    1
         Death
    4
    3
    6
         Progressive Disease
    22
    9
    34
         Withdrawal by Subject
    1
    3
    3
         Clinical Progression
    6
    6
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: HER2 Overexpressing
    Reporting group description
    		 Participants with HER2-overexpressing(immunohistochemistry [IHC] 3+ or IHC 2+), unresectable and/or metastatic NSCLC adenocarcinoma who received 6.4 mg/kg trastuzumab deruxtecan (DS-8201a). Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.

    Reporting group title
    Cohort 1a: HER2 Overexpressing
    Reporting group description
    		 Participants with HER2-overexpressing (immunohistochemistry [IHC] 3+ or IHC 2+), unresectable and/or metastatic NSCLC adenocarcinoma who received 5.4 mg/kg trastuzumab deruxtecan (DS-8201a). Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.

    Reporting group title
    Cohort 2: HER2 Mutated
    Reporting group description
    		 Participants with HER2-mutated, unresectable and/or metastatic NSCLC who received 6.4 mg/kg trastuzumab deruxtecan (DS-8201a). Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.

    Reporting group values
    		 Cohort 1: HER2 Overexpressing Cohort 1a: HER2 Overexpressing Cohort 2: HER2 Mutated Total
    Number of subjects
    		 49 41 91 181
    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)
    		 27 27 55 109
        From 65-84 years
    		 21 14 35 70
        85 years and over
    		 1 0 1 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.2 ± 9.58 60.3 ± 10.22 60.3 ± 11.94 -
    Gender categorical
    Units: Subjects
        Female
    		 19 19 60 98
        Male
    		 30 22 31 83
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 1
        Asian
    		 13 4 31 48
        Black or African American
    		 4 2 1 7
        White
    		 31 31 40 102
        Unknown or Not Reported
    		 1 3 19 23

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: HER2 Overexpressing
    Reporting group description
    		 Participants with HER2-overexpressing(immunohistochemistry [IHC] 3+ or IHC 2+), unresectable and/or metastatic NSCLC adenocarcinoma who received 6.4 mg/kg trastuzumab deruxtecan (DS-8201a). Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.

    Reporting group title
    Cohort 1a: HER2 Overexpressing
    Reporting group description
    		 Participants with HER2-overexpressing (immunohistochemistry [IHC] 3+ or IHC 2+), unresectable and/or metastatic NSCLC adenocarcinoma who received 5.4 mg/kg trastuzumab deruxtecan (DS-8201a). Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.

    Reporting group title
    Cohort 2: HER2 Mutated
    Reporting group description
    		 Participants with HER2-mutated, unresectable and/or metastatic NSCLC who received 6.4 mg/kg trastuzumab deruxtecan (DS-8201a). Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.

    Primary: Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC)

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    End point title
    		 Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) [1]
    End point description
    The Objective Response Rate (ORR) was the defined as the percentage of participants who achieved a best overall response of confirmed Complete Response (CR) or Partial Response (PR), assessed by independent central review (ICR) committee 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 ICR is reported. Objective response rate was assessed in the Full Analysis Set at data cut-off date of 03 May 2021.
    End point type
    Primary
    End point timeframe
    Up to 36 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 for end point.
    End point values
    		 Cohort 1: HER2 Overexpressing Cohort 1a: HER2 Overexpressing Cohort 2: HER2 Mutated
    Number of subjects analysed
    49
    41
    91
    Units: Percentage of Participants
        number (confidence interval 95%)
    26.5 (15.0 to 41.1)
    29.3 (16.1 to 45.5)
    54.9 (44.2 to 65.4)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC)

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    End point title
    		 Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC)
    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 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 investigator assessment is reported. Objective response rate was assessed in the Full Analysis Set at data cut-off date of 03 May 2021.
    End point type
    Secondary
    End point timeframe
    Up to 36 months (data cut-off)
    End point values
    		 Cohort 1: HER2 Overexpressing Cohort 1a: HER2 Overexpressing Cohort 2: HER2 Mutated
    Number of subjects analysed
    49
    41
    91
    Units: Percentage of Participants
        number (confidence interval 95%)
    28.6 (16.6 to 43.3)
    31.7 (18.1 to 48.1)
    61.5 (50.8 to 71.6)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or - Mutated Non-Small-Cell Lung Cancer (NSCLC)

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    End point title
    		 Duration of Response (DoR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or - Mutated Non-Small-Cell Lung Cancer (NSCLC)
    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 independent central review 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 03 May 2021.
    End point type
    Secondary
    End point timeframe
    Up to 36 months (data cut-off)
    End point values
    		 Cohort 1: HER2 Overexpressing Cohort 1a: HER2 Overexpressing Cohort 2: HER2 Mutated
    Number of subjects analysed
    13 [2]
    12 [3]
    50 [4]
    Units: months
    median (confidence interval 95%)
        Independent Central Review (ICR)
    5.8 (4.3 to 99.9)
    4.7 (4.0 to 99.9)
    9.3 (5.7 to 14.7)
        Investigator Assessment (IA)
    5.8 (4.7 to 99.9)
    7.0 (4.2 to 99.9)
    11.7 (7.2 to 16.9)
    Notes
    [2] - ICR=13 participants, IA=11 participants, 99.9 = NA due to insufficient number of events
    [3] - ICR=12 participants, IA=3 participants, 99.9 = NA due to insufficient number of events
    [4] - ICR=50 participants, IA=30 participants
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or - Mutated Non-Small-Cell Lung Cancer (NSCLC)

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    End point title
    		 Progression-Free Survival (PFS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or - Mutated Non-Small-Cell Lung Cancer (NSCLC)
    End point description
    Progression-free survival (PFS) 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. PFS based on independent central review and investigator assessment is reported. Progression-free survival (PFS) was assessed in the Full Analysis Set at data cut-off date of 03 May 2021.
    End point type
    Secondary
    End point timeframe
    Up to 36 months (data cut-off)
    End point values
    		 Cohort 1: HER2 Overexpressing Cohort 1a: HER2 Overexpressing Cohort 2: HER2 Mutated
    Number of subjects analysed
    49
    41 [5]
    91
    Units: months
    median (confidence interval 95%)
        Independent Central Review (ICR)
    5.7 (2.8 to 7.2)
    6.7 (4.5 to 99.9)
    8.2 (6.0 to 11.9)
        Investigator Assessment (IA)
    5.7 (3.8 to 7.2)
    7.2 (4.1 to 8.4)
    9.3 (7.1 to 14.0)
    Notes
    [5] - 99.9 = NA due to insufficient number of events
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non- Small-Cell Lung Cancer (NSCLC)

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    End point title
    		 Overall Survival (OS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non- Small-Cell Lung Cancer (NSCLC)
    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 03 May 2021.
    End point type
    Secondary
    End point timeframe
    Up to 36 months (data cut-off)
    End point values
    		 Cohort 1: HER2 Overexpressing Cohort 1a: HER2 Overexpressing Cohort 2: HER2 Mutated
    Number of subjects analysed
    49
    41 [6]
    91
    Units: months
        median (confidence interval 95%)
    12.4 (7.8 to 17.2)
    99.9 (6.7 to 99.9)
    17.8 (13.8 to 22.1)
    Notes
    [6] - 99.9=NA due to insufficient number of events
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Disease Control Rate (DCR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC)

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    End point title
    		 Percentage of Participants With Disease Control Rate (DCR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC)
    End point description
    Disease Control Rate (DCR) was defined as the percentage of participants who achieved a best overall response of CR, PR, or stable disease (SD) during study treatment. Confirmation of CR/PR was required. DCR based on independent central review and investigator assessment is reported. Disease control rate was assessed in the Full Analysis Set at data cut-off date of 03 May 2021.
    End point type
    Secondary
    End point timeframe
    Up to 36 months (data cut-off)
    End point values
    		 Cohort 1: HER2 Overexpressing Cohort 1a: HER2 Overexpressing Cohort 2: HER2 Mutated
    Number of subjects analysed
    49
    41
    91
    Units: Percentage of Participants
    number (confidence interval 95%)
        Independent Central Review (ICR)
    68.9 (53.4 to 81.8)
    77.5 (61.6 to 89.2)
    93.0 (85.4 to 97.4)
        Investigator Assessment (IA)
    75.5 (61.1 to 86.7)
    78.0 (62.4 to 89.4)
    94.5 (87.6 to 98.2)
    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 36 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
    Cohort 1: HER2 Overexpressing
    Reporting group description
    		 Participants with HER2-overexpressing(immunohistochemistry [IHC] 3+ or IHC 2+), unresectable and/or metastatic NSCLC adenocarcinoma who received 6.4 mg/kg trastuzumab deruxtecan (DS-8201a). Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.

    Reporting group title
    Cohort 1a: HER2 Overexpressing
    Reporting group description
    		 Participants with HER2-overexpressing (immunohistochemistry [IHC] 3+ or IHC 2+), unresectable and/or metastatic NSCLC adenocarcinoma who received 5.4 mg/kg trastuzumab deruxtecan (DS-8201a). Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.

    Reporting group title
    Cohort 2: HER2 Mutated
    Reporting group description
    		 Participants with HER2-mutated, unresectable and/or metastatic NSCLC who received 6.4 mg/kg trastuzumab deruxtecan (DS-8201a). Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.

    Serious adverse events
    		 Cohort 1: HER2 Overexpressing Cohort 1a: HER2 Overexpressing Cohort 2: HER2 Mutated
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 49 (55.10%)
    14 / 41 (34.15%)
    39 / 91 (42.86%)
         number of deaths (all causes)
    35
    11
    47
         number of deaths resulting from adverse events
    10
    5
    13
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm Malignant
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 41 (2.44%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 41 (2.44%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 41 (2.44%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Disease Progression
         subjects affected / exposed
    6 / 49 (12.24%)
    3 / 41 (7.32%)
    7 / 91 (7.69%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 6
    0 / 3
    0 / 7
    Fatigue
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 41 (2.44%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 41 (2.44%)
    0 / 91 (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
    Oedema Peripheral
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 41 (2.44%)
    0 / 91 (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
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 41 (2.44%)
    7 / 91 (7.69%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
    8 / 8
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Interstitial lung disease
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    3 / 91 (3.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 41 (2.44%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute Pulmonary Oedema
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 41 (2.44%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 41 (4.88%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Haemoptysis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental Status Changes
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Troponin I Increased
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin Increased
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram T Wave Abnormal
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 41 (2.44%)
    0 / 91 (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
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiation Necrosis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Transfusion Reaction
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Myocardial Infarction
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         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 / 49 (0.00%)
    1 / 41 (2.44%)
    0 / 91 (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
    Nervous system disorders
    Respiratory Failure
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Seizure
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    3 / 91 (3.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Central Nervous System Necrosis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic Encephalopathy
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Partial Seizures
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 41 (2.44%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal Stenosis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Motility Disorder
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Ileus
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Intestinal Perforation
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Intra-Abdominal Haematoma
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    2 / 49 (4.08%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal Obstruction
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Haemorrhage
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 41 (2.44%)
    3 / 91 (3.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 41 (2.44%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 41 (2.44%)
    0 / 91 (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
    Infections and infestations
    Abdominal Sepsis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Covid-19 Pneumonia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 41 (2.44%)
    0 / 91 (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
    Empyema
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 41 (2.44%)
    0 / 91 (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
    Enterocolitis Infectious
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Oesophageal Infection
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 41 (2.44%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Staphylococcal
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    1 / 49 (2.04%)
    1 / 41 (2.44%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 41 (2.44%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal Bacteraemia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    0 / 91 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: HER2 Overexpressing Cohort 1a: HER2 Overexpressing Cohort 2: HER2 Mutated
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 49 (93.88%)
    41 / 41 (100.00%)
    91 / 91 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    5 / 91 (5.49%)
         occurrences all number
    0
    0
    5
    Hypotension
         subjects affected / exposed
    4 / 49 (8.16%)
    0 / 41 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    4
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    16 / 49 (32.65%)
    20 / 41 (48.78%)
    30 / 91 (32.97%)
         occurrences all number
    24
    23
    37
    Asthenia
         subjects affected / exposed
    6 / 49 (12.24%)
    6 / 41 (14.63%)
    16 / 91 (17.58%)
         occurrences all number
    6
    6
    22
    Malaise
         subjects affected / exposed
    9 / 49 (18.37%)
    3 / 41 (7.32%)
    12 / 91 (13.19%)
         occurrences all number
    10
    3
    16
    Pyrexia
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 41 (2.44%)
    16 / 91 (17.58%)
         occurrences all number
    1
    1
    19
    Oedema Peripheral
         subjects affected / exposed
    2 / 49 (4.08%)
    4 / 41 (9.76%)
    11 / 91 (12.09%)
         occurrences all number
    2
    4
    13
    Non-Cardiac Chest Pain
         subjects affected / exposed
    3 / 49 (6.12%)
    4 / 41 (9.76%)
    3 / 91 (3.30%)
         occurrences all number
    3
    4
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    9 / 49 (18.37%)
    8 / 41 (19.51%)
    17 / 91 (18.68%)
         occurrences all number
    9
    8
    18
    Cough
         subjects affected / exposed
    6 / 49 (12.24%)
    11 / 41 (26.83%)
    14 / 91 (15.38%)
         occurrences all number
    7
    12
    14
    Pneumonitis
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 41 (2.44%)
    12 / 91 (13.19%)
         occurrences all number
    5
    1
    12
    Epistaxis
         subjects affected / exposed
    4 / 49 (8.16%)
    3 / 41 (7.32%)
    8 / 91 (8.79%)
         occurrences all number
    4
    3
    8
    Hiccups
         subjects affected / exposed
    4 / 49 (8.16%)
    2 / 41 (4.88%)
    4 / 91 (4.40%)
         occurrences all number
    4
    4
    5
    Productive Cough
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 41 (4.88%)
    5 / 91 (5.49%)
         occurrences all number
    0
    2
    7
    Rhinorrhoea
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 41 (2.44%)
    1 / 91 (1.10%)
         occurrences all number
    3
    1
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 49 (4.08%)
    0 / 41 (0.00%)
    12 / 91 (13.19%)
         occurrences all number
    2
    0
    12
    Anxiety
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 41 (7.32%)
    8 / 91 (8.79%)
         occurrences all number
    1
    4
    8
    Depression
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    5 / 91 (5.49%)
         occurrences all number
    0
    0
    5
    Investigations
    Neutrophil Count Decreased
         subjects affected / exposed
    11 / 49 (22.45%)
    2 / 41 (4.88%)
    27 / 91 (29.67%)
         occurrences all number
    18
    3
    62
    White Blood Cell Count Decreased
         subjects affected / exposed
    6 / 49 (12.24%)
    1 / 41 (2.44%)
    17 / 91 (18.68%)
         occurrences all number
    14
    1
    50
    Lymphocyte Count Decreased
         subjects affected / exposed
    5 / 49 (10.20%)
    1 / 41 (2.44%)
    13 / 91 (14.29%)
         occurrences all number
    11
    1
    30
    Weight Decreased
         subjects affected / exposed
    12 / 49 (24.49%)
    6 / 41 (14.63%)
    21 / 91 (23.08%)
         occurrences all number
    12
    6
    24
    Alanine Aminotransferase Increased
         subjects affected / exposed
    5 / 49 (10.20%)
    3 / 41 (7.32%)
    14 / 91 (15.38%)
         occurrences all number
    5
    3
    23
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    6 / 49 (12.24%)
    2 / 41 (4.88%)
    17 / 91 (18.68%)
         occurrences all number
    7
    2
    20
    Platelet Count Decreased
         subjects affected / exposed
    7 / 49 (14.29%)
    2 / 41 (4.88%)
    11 / 91 (12.09%)
         occurrences all number
    7
    2
    19
    Blood Creatinine Increased
         subjects affected / exposed
    5 / 49 (10.20%)
    3 / 41 (7.32%)
    4 / 91 (4.40%)
         occurrences all number
    6
    3
    4
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 41 (2.44%)
    5 / 91 (5.49%)
         occurrences all number
    3
    1
    5
    Electrocardiogram Qt Prolonged
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    6 / 91 (6.59%)
         occurrences all number
    0
    0
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 49 (20.41%)
    3 / 41 (7.32%)
    8 / 91 (8.79%)
         occurrences all number
    11
    4
    9
    Headache
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 41 (4.88%)
    15 / 91 (16.48%)
         occurrences all number
    3
    2
    16
    Dysgeusia
         subjects affected / exposed
    4 / 49 (8.16%)
    3 / 41 (7.32%)
    12 / 91 (13.19%)
         occurrences all number
    4
    3
    12
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    5 / 91 (5.49%)
         occurrences all number
    1
    0
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 49 (28.57%)
    10 / 41 (24.39%)
    32 / 91 (35.16%)
         occurrences all number
    17
    11
    45
    Neutropenia
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 41 (4.88%)
    6 / 91 (6.59%)
         occurrences all number
    3
    2
    9
    Eye disorders
    Dry Eye
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 41 (4.88%)
    7 / 91 (7.69%)
         occurrences all number
    0
    2
    7
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    28 / 49 (57.14%)
    30 / 41 (73.17%)
    68 / 91 (74.73%)
         occurrences all number
    37
    68
    120
    Diarrhoea
         subjects affected / exposed
    13 / 49 (26.53%)
    13 / 41 (31.71%)
    37 / 91 (40.66%)
         occurrences all number
    17
    21
    66
    Vomiting
         subjects affected / exposed
    13 / 49 (26.53%)
    12 / 41 (29.27%)
    41 / 91 (45.05%)
         occurrences all number
    16
    15
    65
    Constipation
         subjects affected / exposed
    15 / 49 (30.61%)
    10 / 41 (24.39%)
    34 / 91 (37.36%)
         occurrences all number
    16
    10
    38
    Abdominal pain
         subjects affected / exposed
    2 / 49 (4.08%)
    5 / 41 (12.20%)
    8 / 91 (8.79%)
         occurrences all number
    3
    5
    8
    Stomatitis
         subjects affected / exposed
    6 / 49 (12.24%)
    1 / 41 (2.44%)
    6 / 91 (6.59%)
         occurrences all number
    6
    2
    7
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    2 / 49 (4.08%)
    1 / 41 (2.44%)
    8 / 91 (8.79%)
         occurrences all number
    2
    1
    8
    Dyspepsia
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 41 (4.88%)
    6 / 91 (6.59%)
         occurrences all number
    0
    2
    6
    Dysphagia
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 41 (0.00%)
    5 / 91 (5.49%)
         occurrences all number
    3
    0
    5
    Abdominal Pain Upper
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 41 (0.00%)
    4 / 91 (4.40%)
         occurrences all number
    3
    0
    4
    Haemorrhoids
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    7 / 91 (7.69%)
         occurrences all number
    0
    0
    7
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    5 / 91 (5.49%)
         occurrences all number
    0
    0
    5
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    10 / 49 (20.41%)
    5 / 41 (12.20%)
    42 / 91 (46.15%)
         occurrences all number
    10
    6
    42
    Dry skin
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 41 (0.00%)
    11 / 91 (12.09%)
         occurrences all number
    1
    0
    11
    Pruritus
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 41 (2.44%)
    6 / 91 (6.59%)
         occurrences all number
    1
    1
    6
    Rash Maculo-Papular
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    6 / 91 (6.59%)
         occurrences all number
    0
    0
    7
    Eczema
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 41 (0.00%)
    5 / 91 (5.49%)
         occurrences all number
    0
    0
    5
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    2 / 49 (4.08%)
    5 / 41 (12.20%)
    15 / 91 (16.48%)
         occurrences all number
    2
    5
    15
    Arthralgia
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 41 (0.00%)
    12 / 91 (13.19%)
         occurrences all number
    4
    0
    13
    Myalgia
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 41 (0.00%)
    6 / 91 (6.59%)
         occurrences all number
    3
    0
    6
    Muscular Weakness
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 41 (4.88%)
    5 / 91 (5.49%)
         occurrences all number
    0
    3
    5
    Muscle Spasms
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 41 (4.88%)
    2 / 91 (2.20%)
         occurrences all number
    3
    2
    2
    Pain In Extremity
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 41 (7.32%)
    2 / 91 (2.20%)
         occurrences all number
    0
    3
    2
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 49 (10.20%)
    1 / 41 (2.44%)
    15 / 91 (16.48%)
         occurrences all number
    6
    1
    18
    Urinary Tract Infection
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 41 (4.88%)
    9 / 91 (9.89%)
         occurrences all number
    4
    4
    9
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    22 / 49 (44.90%)
    19 / 41 (46.34%)
    32 / 91 (35.16%)
         occurrences all number
    23
    20
    39
    Hypokalaemia
         subjects affected / exposed
    8 / 49 (16.33%)
    3 / 41 (7.32%)
    11 / 91 (12.09%)
         occurrences all number
    13
    4
    18
    Hypomagnesaemia
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 41 (2.44%)
    4 / 91 (4.40%)
         occurrences all number
    4
    1
    5
    Dehydration
         subjects affected / exposed
    2 / 49 (4.08%)
    3 / 41 (7.32%)
    2 / 91 (2.20%)
         occurrences all number
    4
    3
    2
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 41 (2.44%)
    7 / 91 (7.69%)
         occurrences all number
    1
    1
    7
    Hyponatraemia
         subjects affected / exposed
    2 / 49 (4.08%)
    3 / 41 (7.32%)
    4 / 91 (4.40%)
         occurrences all number
    2
    3
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Feb 2018
    Updated all sections to replace drug name (DS-8201a) with international non-proprietary name (trastuzumab deruxtecan). Updated inclusion & exclusion criteria, risk and benefits section, and dose modification section. Added guidance and threshold requirements for troponin repeat testing. Updated clinical summary and management guidance for adverse events of special interests. Clarified details related to pregnancy screening.
    19 Mar 2018
    Modified inclusion criteria to exclude subjects with hepatic impairment. Added ophthalmologic assessment at End of Treatment visit in the Schedule of Events table and footnote.
    02 May 2019
    Updated enrollment period, inclusion & exclusion criteria, and dose modification sections. Clarified Follow-up Phase details. Updated sections "Other Non-Hematologic Toxicity" and "Prohibited Medications & Treatment". Updated Screening, End of Treatment, Electrocardiograms, PK, Tumor & Blood Biomarker Assessments, and Immunogenicity Sections. Updated the Interstitial Lung Disease/Pneumonitis management guidance. Updated the primary analysis and interim analysis sections along with the Schedule of Events tables.
    12 Aug 2019
    Updated International Non-proprietary Name (INN) to (fam)-trastuzumab deruxtecan. Updated overall design related to increases in enrollment number and study duration. Clarified details for Follow-up Phase. Updated interim analysis, inclusion criteria, method of treatment allocation, dose modification, and study procedures sections. For Cohort 1 only, tissue screening procedures updated. Updated general statistical considerations , sample size determination, and statistical analysis process sections. Added list of HER2 mutations and references related to rationale for expansion and size determination.
    21 Feb 2020
    Updated protocol synopsis, duration of study, clinical experience, summary of Clinical PK, rationale for expansion, and risks & benefits sections. Updated overall design section to include additional Cohort 1a. Updated selection of dose & usage, interim analysis, and inclusion & exclusion criteria sections. Updated Management Guidelines for Trastuzumab Deruxtecan, Guidelines for Non-Hematologic Toxicities, and Guidance for Interstitial Lung Disease. Updated study procedures, schedule of events, immunogenicity, LVEF decrease, and serious adverse reporting procedure for investigators sections. Removed infusion-related reactions section. Added guidance to the sponsor on reporting on Sudden Unexpected Serious Adverse Reactions (SUSARs) in Japan.
    21 Feb 2020
    This amendment is primarily driven by the need for alignment with the latest safety information on trastuzumab deruxtecan; additional information on Coronavirus disease 2019 (COVID-19) and update to interstitial lung disease (ILD) management. Updated protocol synopsis, inclusion & exclusion criteria, sample dose reduction level and interruption guidelines, dose modification, prior & concomitant medications, and additional PK assessment sections updated. Updated safety sections to provide clarifications. Updates efficacy analysis, immunogencity analysis, AE analysis, and general statistical considerations sections. Updated schedule of events and instructions related to COVID-19.

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

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

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