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    Clinical Trial Results:
    A phase 3, multicenter, randomized, open-label, active-controlled trial of trastuzumab deruxtecan (T-DXd), an anti-HER2-antibody drug conjugate (ADC), versus treatment of physician’s choice for HER2-Low, unresectable and/or metastatic breast cancer subjects (DESTINY-Breast04)

    Summary
    EudraCT number
    		 2018-003069-33
    Trial protocol
    		 BE   SE   GR   PT   DE   ES   GB   HU  
    Global end of trial date

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

    Trial information

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    Trial identification
    Sponsor protocol code
    DS8201-A-U303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03734029
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    211 Mount Airy Rd, Basking Ridge, United States, 07920
    Public contact
    Contact for Clinical Trial Information, Daiichi Sankyo, Inc., +1 908-992-6400, CTRinfo@dsi.com
    Scientific contact
    Contact for Clinical Trial Information, Daiichi Sankyo, Inc., +1 908-992-6400, CTRinfo@dsi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    11 Jan 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jan 2022
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To compare the progression-free survival (PFS) benefit of T-DXd to physician’s choice in HER2-low, hormone receptor (HR)-positive breast cancer, based on blinded independent central review (BICR).
    Protection of trial subjects
    The study protocol, amendments, informed consent form(s) (ICFs), and information sheets were approved by the appropriate and applicable IECs or IRBs. This study was conducted in compliance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Council for Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and applicable regulatory requirement(s).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Dec 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    China: 62
    Country: Number of subjects enrolled
    Israel: 20
    Country: Number of subjects enrolled
    Japan: 85
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 57
    Country: Number of subjects enrolled
    Switzerland: 14
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    United States: 89
    Country: Number of subjects enrolled
    Portugal: 16
    Country: Number of subjects enrolled
    Spain: 48
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    France: 56
    Country: Number of subjects enrolled
    Greece: 21
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Italy: 30
    Worldwide total number of subjects
    557
    EEA total number of subjects
    202
    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)
    426
    From 65 to 84 years
    131
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 557 participants were enrolled and randomized to treatment at 161 study sites in the US (27 sites), Japan (18), France (16), China (15), Italy (13), Spain (12), Greece (8), Portugal (8), Republic of Korea (8), Israel (6), Switzerland (6), Austria (4), Belgium (4), Russia (3), Sweden (3), Taiwan (3), UK (3), Canada (2), and Hungary (2).

    Pre-assignment
    Screening details
    		 All participants had been previously treated with at least 1 and no more than 2 prior lines of chemotherapy in the recurrent or metastatic setting. The treatment chosen for the Physician’s Choice arm was based on the label approved in the country of drug administration. The Physician's Choice group was combined to ensure an appropriate sample size.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Randomized, open label study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trastuzumab Deruxtecan (T-DXd)
    Arm description
    		 Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to DS8201a with an initial dose of 5.4 mg/kg was infused for approximately 90 minutes. If there was no infusion-related reaction (IRR), doses of T-DXd after the initial dose of 5.4 mg/kg were infused for a minimum of 30 minutes.
    Arm type
    		 Experimental

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

    Arm title
    		 Physician's Choice
    Arm description
    		 Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician’s choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nabpaclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000-1250 mg/m2 PO twice daily on Days 1-14; cycled every 21 days

    Investigational medicinal product name
    Eribulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m^2 IV on Days 1 and 8; cycled every 21 days (Refers to eribulin mesylate [1.23 mg eribulin base = 1.4 mg eribulin mesylate])

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Option 1: 800-1200 mg/m^2 IV on Days 1 and 8; cycled every 21 days Option 2: 800-1200 mg/m^2 IV on Days 1, 8, and 15; cycled every 28 days

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Option 1: 175 mg/m^2 IV on Day 1; cycled every 21 days Option 2: 80 mg/m^2 IV on Day 1 weekly

    Investigational medicinal product name
    Nab-paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Option 1: 260 mg/m2 IV; cycled every 21 days Option 2: 100 mg/m2 or 125 mg/m2 IV on Days 1, 8, and 15; cycled every 28 days

    Number of subjects in period 1
    		Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Started
    373
    184
    Completed
    58
    3
    Not completed
    315
    181
         Consent withdrawn by subject
    12
    11
         Physician decision
    4
    3
         Randomized, but not treated
    2
    12
         Adverse event, non-fatal
    60
    14
         Clinical progression by investigator
    10
    8
         Death
    5
    2
         Not specified
    2
    -
         Lost to follow-up
    -
    1
         Progressive disease as per RECIST v1.1
    220
    130

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trastuzumab Deruxtecan (T-DXd)
    Reporting group description
    		 Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to DS8201a with an initial dose of 5.4 mg/kg was infused for approximately 90 minutes. If there was no infusion-related reaction (IRR), doses of T-DXd after the initial dose of 5.4 mg/kg were infused for a minimum of 30 minutes.

    Reporting group title
    Physician's Choice
    Reporting group description
    		 Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician’s choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nabpaclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.

    Reporting group values
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice Total
    Number of subjects
    		 373 184 557
    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)
    		 290 136 426
        From 65-84 years
    		 83 48 131
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.5 ( 10.6 ) 56.5 ( 11.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 371 184 555
        Male
    		 2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Trastuzumab Deruxtecan (T-DXd)
    Reporting group description
    		 Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to DS8201a with an initial dose of 5.4 mg/kg was infused for approximately 90 minutes. If there was no infusion-related reaction (IRR), doses of T-DXd after the initial dose of 5.4 mg/kg were infused for a minimum of 30 minutes.

    Reporting group title
    Physician's Choice
    Reporting group description
    		 Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician’s choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nabpaclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.

    Primary: Progression-free Survival (PFS) Based on Blinded Independent Central Review (BICR) in the Hormone Receptor- Positive Cohort in Participants With HER2-low Breast Cancer

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    End point title
    		 Progression-free Survival (PFS) Based on Blinded Independent Central Review (BICR) in the Hormone Receptor- Positive Cohort in Participants With HER2-low Breast Cancer
    End point description
    Progression-free survival (PFS), defined as at least a 20% increase in the sum of diameters of target lesions, was assessed from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever came first. PFS was based on blinded independent central review (BICR) in the hormone receptorpositive cohort according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1. Median PFS was from Kaplan-Meier analysis. Confidence interval for median was computed using the Brookmeyer-Crowley method.
    End point type
    Primary
    End point timeframe
    From the date of randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, up to approximately 3 years
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Number of subjects analysed
    331
    163
    Units: months
    median (confidence interval 95%)
        Progression-free survival
    10.1 (9.5 to 11.5)
    5.4 (4.4 to 7.1)
    Statistical analysis title
    		 Trastuzumab Deruxtecan (T-DXd), Physician's Choice
    Comparison groups
    Trastuzumab Deruxtecan (T-DXd) v Physician's Choice
    Number of subjects included in analysis
    494
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.5085
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4012
         upper limit
    		 0.6444
    Notes
    [1] - Two-sided p-value from stratified log-rank test, Hazard ratio and 95% CI from stratified Cox proportional hazards model using stratification factors: HER2 status, number of prior lines of chemotherapy, hormone Receptor/CDK status, as defined by IXR

    Secondary: Progression-free Survival (PFS) Based on Blinded Independent Central Review (BICR) in Participants With HER2-low Breast Cancer (All Patients) Regardless of Hormone Receptor Status

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    End point title
    		 Progression-free Survival (PFS) Based on Blinded Independent Central Review (BICR) in Participants With HER2-low Breast Cancer (All Patients) Regardless of Hormone Receptor Status
    End point description
    Progression-free survival (PFS), defined as at least a 20% increase in the sum of diameters of target lesions, was assessed from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever came first. PFS was based on blinded independent central review (BICR) according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1. Median PFS was from Kaplan-Meier analysis. Confidence interval for median was computed using the Brookmeyer-Crowley method.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, up to approximately 3 years
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Number of subjects analysed
    373
    184
    Units: months
    median (confidence interval 95%)
        Progression-free survival
    9.9 (9.0 to 11.3)
    5.1 (4.2 to 6.8)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer

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    End point title
    		 Overall Survival (OS) in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer
    End point description
    Overall survival (OS) was defined as the time from the date of randomization to the date of death due to any cause. If there was no death reported for a participant before the data cutoff for OS analysis, OS was censored at the last contact date at which the participant was known to be alive.
    End point type
    Secondary
    End point timeframe
    From the date of randomization up to the date of death due to any cause, up to approximately 3 years
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Number of subjects analysed
    331
    163
    Units: months
    median (confidence interval 95%)
        Overall survival
    23.9 (20.8 to 24.8)
    17.5 (15.2 to 22.4)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in Participants With HER2-low Breast Cancer (All Patients)

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    End point title
    		 Overall Survival (OS) in Participants With HER2-low Breast Cancer (All Patients)
    End point description
    Overall survival (OS) was defined as the time from the date of randomization to the date of death due to any cause. If there was no death reported for a participant before the data cutoff for OS analysis, OS was censored at the last contact date at which the participant was known to be alive.
    End point type
    Secondary
    End point timeframe
    From the date of randomization up to the date of death due to any cause, up to approximately 3 years
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Number of subjects analysed
    373
    184
    Units: months
    median (confidence interval 95%)
        Overall survival
    23.4 (20.0 to 24.8)
    16.8 (14.5 to 20.0)
    No statistical analyses for this end point

    Secondary: Progression-free Survival Based on Investigator Assessment in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer

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    End point title
    		 Progression-free Survival Based on Investigator Assessment in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer
    End point description
    Progression-free survival (PFS), defined as at least a 20% increase in the sum of diameters of target lesions, was assessed from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever came first. PFS was based on investigator assessment in the hormone receptor-positive cohort according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1. Median PFS was from Kaplan-Meier analysis. Confidence interval for median was computed using the Brookmeyer-Crowley method.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, up to approximately 3 years
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Number of subjects analysed
    331
    163
    Units: months
    median (confidence interval 95%)
        Progression-free survival
    9.6 (8.4 to 10.0)
    4.2 (3.4 to 4.9)
    No statistical analyses for this end point

    Secondary: Progression-free Survival Based on Investigator Assessment in Participants With HER2-low Breast Cancer (All Patients)

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    End point title
    		 Progression-free Survival Based on Investigator Assessment in Participants With HER2-low Breast Cancer (All Patients)
    End point description
    Progression-free survival (PFS), defined as at least a 20% increase in the sum of diameters of target lesions, was assessed from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever came first. PFS was based on investigator assessment according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1. Median PFS was from Kaplan-Meier analysis. Confidence interval for median was computed using the Brookmeyer-Crowley method.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, up to approximately 3 years
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Number of subjects analysed
    373
    184
    Units: months
    median (confidence interval 95%)
        Progression-free survival
    8.8 (8.3 to 9.8)
    4.2 (3.0 to 4.5)
    No statistical analyses for this end point

    Secondary: Best Overall Response and Confirmed Objective Response Rate (ORR) in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer

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    End point title
    		 Best Overall Response and Confirmed Objective Response Rate (ORR) in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer
    End point description
    Best overall response rate and confirmed objective response rate (ORR) were assessed by blinded independent central review (BICR) and investigator assessment. Complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. Confirmed ORR is defined as the number of patients with complete and partial response and confirmed with a second assessment.
    End point type
    Secondary
    End point timeframe
    From screening and every 6 weeks up to withdrawal of subject consent, progressive disease (PD), or unacceptable toxicity, up to approximately 3 years
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Number of subjects analysed
    331
    163
    Units: patients
    number (not applicable)
        BICR: Complete response
    12
    1
        BICR: Partial response
    164
    26
        BICR: Stable disease
    115
    81
        BICR: Progressive disease
    26
    34
        BICR: Not evaluable
    14
    21
        Investigator: Complete response
    5
    0
        Investigator: Partial response
    163
    30
        Investigator: Stable disease
    124
    80
        Investigator: Progressive disease
    28
    34
        Investigator: Not evaluable
    11
    19
        BICR: Objective response rate
    175
    27
        Investigator: Objective response rate
    168
    30
    No statistical analyses for this end point

    Secondary: Best Overall Response and Confirmed Objective Response Rate (ORR) in Participants With HER2-low Breast Cancer (All Patients)

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    End point title
    		 Best Overall Response and Confirmed Objective Response Rate (ORR) in Participants With HER2-low Breast Cancer (All Patients)
    End point description
    Best overall response rate and confirmed objective response rate (ORR) were assessed by blinded independent central review (BICR) and investigator assessment. Complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. Confirmed ORR is defined as the number of patients with complete and partial response and confirmed with a second assessment.
    End point type
    Secondary
    End point timeframe
    From screening and every 6 weeks up to withdrawal of subject consent, progressive disease (PD), or unacceptable toxicity, up to approximately 3 years
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Number of subjects analysed
    373
    184
    Units: patients
    number (not applicable)
        BICR: Complete response
    13
    2
        BICR: Partial response
    183
    28
        BICR: Stable disease
    129
    91
        BICR: Progressive disease
    31
    41
        BICR: Not evaluable
    17
    22
        Investigator: Complete response
    6
    0
        Investigator: Partial response
    187
    31
        Investigator: Stable disease
    135
    93
        Investigator: Progressive disease
    32
    40
        Investigator: Not evaluable
    13
    20
        BICR: Objective response rate
    195
    30
        Investigator: Objective response rate
    193
    31
    No statistical analyses for this end point

    Secondary: Duration of Response in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer

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    End point title
    		 Duration of Response in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer
    End point description
    Duration of Response (DoR) is defined as the date of the first documented objective response (complete response [CR] or partial response [PR]) to the first documented disease progression or death, whichever occurs first. DoR was based on blinded independent central review (BICR) and investigator assessment. Median was from Kaplan-Meier estimate. Confidence interval for median was computed using the Brookmeyer-Crowley method.
    End point type
    Secondary
    End point timeframe
    From the date of the first documented objective response (CR or PR) to the first documented disease progression or death, whichever occurs first, up to approximately 3 years
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Number of subjects analysed
    331
    163
    Units: months
    median (confidence interval 95%)
        BICR: DoR
    10.7 (8.5 to 13.7)
    6.8 (6.5 to 9.9)
        Investigator: DoR
    8.3 (7.1 to 11.1)
    5.6 (3.6 to 6.8)
    No statistical analyses for this end point

    Secondary: Duration of Response in Participants With HER2-low Breast Cancer (All Patients)

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    End point title
    		 Duration of Response in Participants With HER2-low Breast Cancer (All Patients)
    End point description
    Duration of Response (DoR) is defined as the date of the first documented objective response (complete response [CR] or partial response [PR]) to the first documented disease progression or death, whichever occurs first. DoR was based on blinded independent central review (BICR) and investigator assessment. Median was from Kaplan-Meier estimate. Confidence interval for median was computed using the Brookmeyer-Crowley method.
    End point type
    Secondary
    End point timeframe
    From the date of the first documented objective response (CR or PR) to the first documented disease progression or death, whichever occurs first, up to approximately 3 years
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Number of subjects analysed
    373
    184
    Units: months
    median (confidence interval 95%)
        BICR: DoR
    10.7 (8.5 to 13.2)
    6.8 (6.0 to 9.9)
        Investigator: DoR
    8.3 (7.0 to 9.9)
    5.6 (3.7 to 6.6)
    No statistical analyses for this end point

    Secondary: Number of Overall Survival Events (Deaths)

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    End point title
    		 Number of Overall Survival Events (Deaths)
    End point description
    End point type
    Secondary
    End point timeframe
    From the date of randomization up to the date of death due to any cause, up to approximately 3 years
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Number of subjects analysed
    373
    184
    Units: events (deaths)
    number (not applicable)
        Overall survival events (deaths)
    149
    90
    No statistical analyses for this end point

    Other pre-specified: All-Cause Mortality

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    End point title
    		 All-Cause Mortality
    End point description
    All-cause mortality in the Safety Analysis Set is defined as all anticipated and unanticipated deaths due to any cause, with the number and frequency of such events by arm or comparison group of the clinical study.
    End point type
    Other pre-specified
    End point timeframe
    From the date of randomization up to the date of death due to any cause, up to approximately 3 years
    End point values
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Number of subjects analysed
    371
    172
    Units: participants
    number (not applicable)
        All-cause mortality
    148
    88
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) were collected from the date of main ICF up to 40 days (+7 days) after the last treatment, whether observed by the investigator or reported by the patient, up to approximately 3 years in the Safety Analysis Set.
    Adverse event reporting additional description
    All-cause mortality was assessed in all randomized participants (Full Analysis Set). The other prespecified outcome measure reports all-cause mortality from the Safety Analysis Set (SAS). Other AEs and SAEs were assessed in the SAS. As prespecified, the Physician’s Choice was based on the approved label per country and combined for analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Trastuzumab Deruxtecan (T-DXd)
    Reporting group description
    		 Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to DS8201a with an initial dose of 5.4 mg/kg was infused for approximately 90 minutes. If there was no infusion-related reaction (IRR), doses of T-DXd after the initial dose of 5.4 mg/kg were infused for a minimum of 30 minutes.

    Reporting group title
    Physician's Choice
    Reporting group description
    		 Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician’s choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nabpaclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.

    Serious adverse events
    		 Trastuzumab Deruxtecan (T-DXd) Physician's Choice
    Total subjects affected by serious adverse events
         subjects affected / exposed
    103 / 371 (27.76%)
    43 / 172 (25.00%)
         number of deaths (all causes)
    149
    90
         number of deaths resulting from adverse events
    14
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 371 (0.27%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava occlusion
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 371 (0.54%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Discomfort
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    2 / 371 (0.54%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Fatigue
         subjects affected / exposed
    1 / 371 (0.27%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 371 (0.54%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (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 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 371 (1.08%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Social problem
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 371 (1.35%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Haemoptysis
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    7 / 371 (1.89%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 371 (0.81%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    7 / 371 (1.89%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary toxicity
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 371 (0.54%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    2 / 371 (0.54%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chemical peritonitis
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 371 (0.00%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medication error
         subjects affected / exposed
    0 / 371 (0.00%)
    3 / 172 (1.74%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 371 (0.00%)
    5 / 172 (2.91%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 371 (0.27%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal obstruction
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Movement disorder
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 371 (1.08%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    4 / 371 (1.08%)
    4 / 172 (2.33%)
         occurrences causally related to treatment / all
    1 / 4
    3 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 371 (0.00%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 371 (0.27%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (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
    0 / 371 (0.00%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Constipation
         subjects affected / exposed
    3 / 371 (0.81%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 371 (1.08%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 371 (1.08%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    2 / 371 (0.54%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 371 (0.27%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Hepatic function abnormal
         subjects affected / exposed
    1 / 371 (0.27%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    2 / 371 (0.54%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 371 (0.54%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 371 (0.27%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    3 / 371 (0.81%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 371 (1.89%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 371 (1.35%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 371 (0.81%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 371 (0.54%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    4 / 371 (1.08%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 371 (0.27%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         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) Physician's Choice
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    366 / 371 (98.65%)
    167 / 172 (97.09%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    75 / 371 (20.22%)
    43 / 172 (25.00%)
         occurrences all number
    107
    58
    Aspartate aminotransferase increased
         subjects affected / exposed
    92 / 371 (24.80%)
    42 / 172 (24.42%)
         occurrences all number
    131
    60
    Blood alkaline phosphatase increased
         subjects affected / exposed
    36 / 371 (9.70%)
    5 / 172 (2.91%)
         occurrences all number
    47
    7
    Blood bilirubin increased
         subjects affected / exposed
    25 / 371 (6.74%)
    7 / 172 (4.07%)
         occurrences all number
    39
    7
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    19 / 371 (5.12%)
    9 / 172 (5.23%)
         occurrences all number
    32
    14
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    20 / 371 (5.39%)
    8 / 172 (4.65%)
         occurrences all number
    22
    9
    Lymphocyte count decreased
         subjects affected / exposed
    29 / 371 (7.82%)
    12 / 172 (6.98%)
         occurrences all number
    68
    16
    Neutrophil count decreased
         subjects affected / exposed
    81 / 371 (21.83%)
    61 / 172 (35.47%)
         occurrences all number
    195
    145
    Platelet count decreased
         subjects affected / exposed
    72 / 371 (19.41%)
    12 / 172 (6.98%)
         occurrences all number
    129
    25
    Weight decreased
         subjects affected / exposed
    59 / 371 (15.90%)
    14 / 172 (8.14%)
         occurrences all number
    61
    15
    White blood cell count decreased
         subjects affected / exposed
    78 / 371 (21.02%)
    49 / 172 (28.49%)
         occurrences all number
    184
    132
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    32 / 371 (8.63%)
    9 / 172 (5.23%)
         occurrences all number
    43
    11
    Dysgeusia
         subjects affected / exposed
    37 / 371 (9.97%)
    16 / 172 (9.30%)
         occurrences all number
    40
    16
    Headache
         subjects affected / exposed
    53 / 371 (14.29%)
    11 / 172 (6.40%)
         occurrences all number
    74
    13
    Neuropathy peripheral
         subjects affected / exposed
    13 / 371 (3.50%)
    16 / 172 (9.30%)
         occurrences all number
    13
    17
    Paraesthesia
         subjects affected / exposed
    8 / 371 (2.16%)
    9 / 172 (5.23%)
         occurrences all number
    10
    10
    Peripheral sensory neuropathy
         subjects affected / exposed
    18 / 371 (4.85%)
    19 / 172 (11.05%)
         occurrences all number
    19
    33
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    137 / 371 (36.93%)
    44 / 172 (25.58%)
         occurrences all number
    204
    59
    Neutropenia
         subjects affected / exposed
    49 / 371 (13.21%)
    29 / 172 (16.86%)
         occurrences all number
    114
    44
    Thrombocytopenia
         subjects affected / exposed
    23 / 371 (6.20%)
    4 / 172 (2.33%)
         occurrences all number
    31
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    69 / 371 (18.60%)
    25 / 172 (14.53%)
         occurrences all number
    116
    30
    Fatigue
         subjects affected / exposed
    110 / 371 (29.65%)
    49 / 172 (28.49%)
         occurrences all number
    154
    58
    Malaise
         subjects affected / exposed
    33 / 371 (8.89%)
    10 / 172 (5.81%)
         occurrences all number
    60
    10
    Oedema peripheral
         subjects affected / exposed
    24 / 371 (6.47%)
    10 / 172 (5.81%)
         occurrences all number
    25
    15
    Pyrexia
         subjects affected / exposed
    42 / 371 (11.32%)
    22 / 172 (12.79%)
         occurrences all number
    51
    33
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    20 / 371 (5.39%)
    5 / 172 (2.91%)
         occurrences all number
    28
    5
    Abdominal pain
         subjects affected / exposed
    35 / 371 (9.43%)
    8 / 172 (4.65%)
         occurrences all number
    47
    8
    Abdominal pain upper
         subjects affected / exposed
    31 / 371 (8.36%)
    13 / 172 (7.56%)
         occurrences all number
    60
    16
    Constipation
         subjects affected / exposed
    124 / 371 (33.42%)
    38 / 172 (22.09%)
         occurrences all number
    205
    40
    Diarrhoea
         subjects affected / exposed
    100 / 371 (26.95%)
    38 / 172 (22.09%)
         occurrences all number
    179
    52
    Dry mouth
         subjects affected / exposed
    26 / 371 (7.01%)
    9 / 172 (5.23%)
         occurrences all number
    28
    9
    Dyspepsia
         subjects affected / exposed
    34 / 371 (9.16%)
    11 / 172 (6.40%)
         occurrences all number
    40
    12
    Gastrooesophageal reflux disease
         subjects affected / exposed
    23 / 371 (6.20%)
    3 / 172 (1.74%)
         occurrences all number
    25
    3
    Nausea
         subjects affected / exposed
    281 / 371 (75.74%)
    52 / 172 (30.23%)
         occurrences all number
    668
    60
    Stomatitis
         subjects affected / exposed
    41 / 371 (11.05%)
    17 / 172 (9.88%)
         occurrences all number
    57
    18
    Vomiting
         subjects affected / exposed
    148 / 371 (39.89%)
    23 / 172 (13.37%)
         occurrences all number
    365
    27
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    35 / 371 (9.43%)
    14 / 172 (8.14%)
         occurrences all number
    41
    16
    Dyspnoea
         subjects affected / exposed
    34 / 371 (9.16%)
    14 / 172 (8.14%)
         occurrences all number
    40
    16
    Epistaxis
         subjects affected / exposed
    39 / 371 (10.51%)
    2 / 172 (1.16%)
         occurrences all number
    46
    2
    Pneumonitis
         subjects affected / exposed
    21 / 371 (5.66%)
    0 / 172 (0.00%)
         occurrences all number
    23
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    147 / 371 (39.62%)
    57 / 172 (33.14%)
         occurrences all number
    153
    59
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    5 / 371 (1.35%)
    24 / 172 (13.95%)
         occurrences all number
    5
    29
    Rash
         subjects affected / exposed
    24 / 371 (6.47%)
    9 / 172 (5.23%)
         occurrences all number
    27
    10
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    24 / 371 (6.47%)
    9 / 172 (5.23%)
         occurrences all number
    26
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    43 / 371 (11.59%)
    20 / 172 (11.63%)
         occurrences all number
    56
    25
    Back pain
         subjects affected / exposed
    33 / 371 (8.89%)
    10 / 172 (5.81%)
         occurrences all number
    42
    12
    Myalgia
         subjects affected / exposed
    22 / 371 (5.93%)
    16 / 172 (9.30%)
         occurrences all number
    28
    22
    Pain in extremity
         subjects affected / exposed
    29 / 371 (7.82%)
    5 / 172 (2.91%)
         occurrences all number
    39
    5
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    27 / 371 (7.28%)
    6 / 172 (3.49%)
         occurrences all number
    30
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    118 / 371 (31.81%)
    33 / 172 (19.19%)
         occurrences all number
    217
    39
    Hypoalbuminaemia
         subjects affected / exposed
    32 / 371 (8.63%)
    8 / 172 (4.65%)
         occurrences all number
    46
    11
    Hypocalcaemia
         subjects affected / exposed
    19 / 371 (5.12%)
    5 / 172 (2.91%)
         occurrences all number
    23
    7
    Hypokalaemia
         subjects affected / exposed
    38 / 371 (10.24%)
    12 / 172 (6.98%)
         occurrences all number
    64
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Nov 2018
    Updated inclusion/exclusion criteria, included definitions for assessments/efficacy outcomes, clarified timing of patient-reported outcome measures, and clarified pharmacokinetic procedures.
    24 Apr 2019
    Updated tissue biopsy procedures, number of study centers, clarified number of HR-negative and HR-postive patients to be enrolled, updated inclusion/exclusion criteria, and expanded medical history.
    23 Apr 2020
    Clarified dose regimen for Physician's Choice arm, added exploratory objective, updated inclusion/exclusion criteria, clarified statistical analysis and tumor assessments, revised study procedures (length of dose delay, withdrawal, screening, pregnancy testing, pharmacokinetic assessments), addressed utilization of patient-reported outcome measures.
    12 Oct 2020
    Addition of new timepoints for overall survival, progression-free survival added as an exploratory objective and endpoint, updated timing of primary analyses.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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