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    Clinical Trial Results:
    A randomized phase II trial of pertuzumab in combination with trastuzumab with or without chemotherapy, both followed by T-DM1 in case of progression, in patients with HER2-positive metastatic breast cancer

    Summary
    EudraCT number
    		 2012-002556-17
    Trial protocol
    		 FR   DE   NL  
    Global end of trial date
    31 May 2020

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

    Trial information

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    Trial identification
    Sponsor protocol code
    SAKK22/10/UC-0140/1207
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01835236
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UNICANCER
    Sponsor organisation address
    101 rue de Tolbiac, Paris, France, 75013
    Public contact
    Nourredine AIT-RAHMOUNE, UNICANCER, 33 1 71 93 67 04, n.ait-rahmoune@unicancer.fr
    Scientific contact
    Jerôme Lemonnier, chef de projets, UNICANCER, 33 1 71 93 67 02, j-lemonnier@unicancer.fr
    Sponsor organisation name
    SAKK
    Sponsor organisation address
    Effingerstrasse 33, Bern, Switzerland, CH-3008
    Public contact
    Sabrina Chiquet, SAKK - SWISS GROUP FOR CLINICAL CANCER RESEARCH, 41 31 389 91 84, sabrina.chiquet@sakk.ch
    Scientific contact
    Sabrina Chiquet, SAKK - SWISS GROUP FOR CLINICAL CANCER RESEARCH, 41 31 389 91 84, sabrina.chiquet@sakk.ch
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Oct 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to evaluate the efficacy in terms of overall survival (OS) at 24 months of a chemotherapy-free dual HER2-inbibition with trastuzumab and pertuzumab (first-line) followed by T-DM1 (second-line) and of a chemotherapy-containing dual HER2-inhibition with trastuzumab and pertuzumab (first-line) followed by T-DM1 (second-line) in patients with HER2-positive metastatic breast cancer.
    Protection of trial subjects
    In order to ensure the protection of the rights, safety and well-being of trial subjects, this clinical trial was conducted in accordance with the Declaration of Helsinki (1964) and subsequent amendments, ICH Good Clinical Practice Guidelines (CPMP/ICH/135/95), the European Directive (2001/20/CE) and the applicable local regulatory requirements and laws. Furthermore, independent Ethics Committees reviewed and gave favorable opinions to the study documents, including the initial protocol and all subsequent amendments, and all information and documents provided to subjects/patients. Written informed consent was obtained from all patients prior to enrollment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    France: 119
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Switzerland: 75
    Worldwide total number of subjects
    210
    EEA total number of subjects
    135
    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)
    126
    From 65 to 84 years
    84
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Pernetta was an international, multicenter, randomized, open label, phase II trial designed to compare the effect of pertuzumab in combination with trastuzumab with or without chemotherapy, both followed by T-DM1 in case of progression, on overall survival at 2 years in patients with HER2-positive metastatic breast cancer.

    Pre-assignment
    Screening details
    		 The trial consisted of a screening phase before randomization to establish eligibility, a treatment phase (3-week treatment cycles; 12 cycles), and a long-term follow-up to monitor overall survival, progression-free survival, time to failure of strategy, objective response, disease control, quality of life, and safety.

    Period 1
    Period 1 title
    First-line treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Chemotherapy-free dual HER2-inbibition
    Arm description
    		 Chemotherapy-free dual HER2-inbibition with trastuzumab and pertuzumab: * Trastuzumab was first administrated (loading dose) at 8 mg/kg by intravenous infusion over 90 min then every 3 weeks at 8 mg/kg by intravenous infusion over 30 to 90 min. * Pertuzumab was first administrated (loading dose) at 840 mg by intravenous infusion over 60 min then every 3 weeks at 420 mg by intravenous infusion over 30 to 90 min. Patients with hormone receptor-positive disease should have received endocrine therapy. Treatment was to be prescribed according to the current guidelines.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was first administrated (loading dose) at 8 mg/kg by intravenous infusion over 90 min then every 3 weeks untill disease progression at 8 mg/kg by intravenous infusion over 30 to 90 min.

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab was first administrated (loading dose) at 840 mg by intravenous infusion over 60 min then every 3 weeks at 420 mg by intravenous infusion over 30 to 90 min. Pertuzumab was administered after a 30-minute observation period following the administration of trastuzumab.

    Arm title
    		 Chemotherapy-containing dual HER2-inbibition
    Arm description
    		 Chemotherapy-containing dual HER2-inbibition with trastuzumab and pertuzumab: HER2-inhibition: * Trastuzumab first administrated (loading dose) at 8 mg/kg by intravenous infusion over 90 min then every 3 weeks at 8 mg/kg by intravenous infusion over 30 to 90 min. PLUS * Pertuzumab first administrated (loading dose) at 840 mg by intravenous infusion over 60 min then every 3 weeks at 420 mg by intravenous infusion over 30 to 90 min. Chemotherapy: * Paclitaxel administrated by intravenous infusion at 90 mg/m2 on day 1, 8, and 15 every 4 weeks for ≥4 months. OR * Vinorelbine first administrated by intravenous infusion at 25 mg/m2 on day 1, 8 then by intravenous infusion at 30 mg/m2 on day 1, 8, and 15 every 3 weeks for ≥4 months. Patients with hormone receptor-positive disease should have received endocrine therapy. Treatment was to be prescribed according to the current guidelines.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was first administrated (loading dose) at 8 mg/kg by intravenous infusion over 90 min then every 3 weeks untill disease progression at 8 mg/kg by intravenous infusion over 30 to 90 min.

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab was first administrated (loading dose) at 840 mg by intravenous infusion over 60 min then every 3 weeks at 420 mg by intravenous infusion over 30 to 90 min. Pertuzumab was administered after a 30-minute observation period following the administration of trastuzumab.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Abraxane
    Pharmaceutical forms
    Powder for dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administrated by intravenous infusion at 90 mg/m2 on day 1, 8, and 15 every 4 weeks for ≥4 months.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    Vinorelbine was first administrated by intravenous infusion at 25 mg/m2 on day 1, 8 then by intravenous infusion at 30 mg/m2 on day 1, 8, and 15 every 3 weeks for ≥4 months.

    Number of subjects in period 1
    		Chemotherapy-free dual HER2-inbibition Chemotherapy-containing dual HER2-inbibition
    Started
    105
    105
    Completed
    64
    47
    Not completed
    41
    58
         Physician decision
    7
    7
         Patient never received treatment
    -
    2
         Secondary malignancy
    -
    1
         HER2 treatment held for >2 administrations
    2
    1
         Sponsor decision
    10
    13
         Consent withdrawn by subject
    1
    2
         Adverse event, non-fatal
    4
    5
         Symptomatic deterioration during 1st-line therapy
    3
    2
         Death
    -
    1
         Unknown
    -
    2
         Radiotherapy of a bone metastasis
    -
    1
         Patient's refusal to continue the treatment
    7
    9
         Symptomatic after PD under 1st-line therapy
    -
    1
         Age-related
    -
    1
         Protocol deviation
    7
    10
    Period 2
    Period 2 title
    Second-line treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 T-DM1
    Arm description
    		 Following disease progression under 1st_line treatment, T-DM1 was administrated every 3 weeks until unacceptable toxicity or disease progression at the dose of 3.6 mg/kg by intravenous infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    T-DM1
    Investigational medicinal product code
    Other name
    Kadcyla
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    T-DM1 was administrated at the dose of 3.6 mg/kg by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression.

    Number of subjects in period 2
    		T-DM1
    Started
    111
    Completed
    7
    Not completed
    104
         Physician decision
    3
         Patient decision
    4
         Disease progression
    75
         Adverse event, non-fatal
    5
         Death
    3
         Secondary malignancy
    2
         Symptomatic deterioration under T-DM1
    6
         Protocol deviation
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Chemotherapy-free dual HER2-inbibition
    Reporting group description
    		 Chemotherapy-free dual HER2-inbibition with trastuzumab and pertuzumab: * Trastuzumab was first administrated (loading dose) at 8 mg/kg by intravenous infusion over 90 min then every 3 weeks at 8 mg/kg by intravenous infusion over 30 to 90 min. * Pertuzumab was first administrated (loading dose) at 840 mg by intravenous infusion over 60 min then every 3 weeks at 420 mg by intravenous infusion over 30 to 90 min. Patients with hormone receptor-positive disease should have received endocrine therapy. Treatment was to be prescribed according to the current guidelines.

    Reporting group title
    Chemotherapy-containing dual HER2-inbibition
    Reporting group description
    		 Chemotherapy-containing dual HER2-inbibition with trastuzumab and pertuzumab: HER2-inhibition: * Trastuzumab first administrated (loading dose) at 8 mg/kg by intravenous infusion over 90 min then every 3 weeks at 8 mg/kg by intravenous infusion over 30 to 90 min. PLUS * Pertuzumab first administrated (loading dose) at 840 mg by intravenous infusion over 60 min then every 3 weeks at 420 mg by intravenous infusion over 30 to 90 min. Chemotherapy: * Paclitaxel administrated by intravenous infusion at 90 mg/m2 on day 1, 8, and 15 every 4 weeks for ≥4 months. OR * Vinorelbine first administrated by intravenous infusion at 25 mg/m2 on day 1, 8 then by intravenous infusion at 30 mg/m2 on day 1, 8, and 15 every 3 weeks for ≥4 months. Patients with hormone receptor-positive disease should have received endocrine therapy. Treatment was to be prescribed according to the current guidelines.

    Reporting group values
    		 Chemotherapy-free dual HER2-inbibition Chemotherapy-containing dual HER2-inbibition Total
    Number of subjects
    		 105 105 210
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 59 (28 to 85) 57 (26 to 81) -
    Gender categorical
    Units: Subjects
        Female
    		 105 105 210
        Male
    		 0 0 0
    WHO performance status
    Units: Subjects
        ECOG 0
    		 61 66 127
        ECOG 1
    		 37 38 75
        ECOG 2
    		 7 1 8
    Hormone receptor status
    Units: Subjects
        Positive
    		 68 66 134
        Negative
    		 37 39 76
    Primary metastatic
    Units: Subjects
        Yes
    		 40 36 76
        No
    		 65 69 134
    Prior chemotherapy
    Units: Subjects
        Yes
    		 53 47 100
        No
    		 52 57 109
        Missing
    		 0 1 1
    Prior anti-HER2 treatment
    Units: Subjects
        Yes
    		 44 42 86
        No
    		 61 62 123
        Missing
    		 0 1 1
    Prior endocrine therapy
    Units: Subjects
        Yes
    		 42 36 78
        No
    		 63 68 131
        Missing
    		 0 1 1
    Weight
    Units: Kg
        median (full range (min-max))
    		 66 (33 to 113) 68 (43 to 125) -
    Height
    Units: cm
        median (full range (min-max))
    		 162 (146 to 180) 163 (146 to 182) -
    Body surface
    Units: m2
        median (full range (min-max))
    		 1.7 (1.2 to 2.3) 1.7 (1.4 to 2.2) -

    End points

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    End points reporting groups
    Reporting group title
    Chemotherapy-free dual HER2-inbibition
    Reporting group description
    		 Chemotherapy-free dual HER2-inbibition with trastuzumab and pertuzumab: * Trastuzumab was first administrated (loading dose) at 8 mg/kg by intravenous infusion over 90 min then every 3 weeks at 8 mg/kg by intravenous infusion over 30 to 90 min. * Pertuzumab was first administrated (loading dose) at 840 mg by intravenous infusion over 60 min then every 3 weeks at 420 mg by intravenous infusion over 30 to 90 min. Patients with hormone receptor-positive disease should have received endocrine therapy. Treatment was to be prescribed according to the current guidelines.

    Reporting group title
    Chemotherapy-containing dual HER2-inbibition
    Reporting group description
    		 Chemotherapy-containing dual HER2-inbibition with trastuzumab and pertuzumab: HER2-inhibition: * Trastuzumab first administrated (loading dose) at 8 mg/kg by intravenous infusion over 90 min then every 3 weeks at 8 mg/kg by intravenous infusion over 30 to 90 min. PLUS * Pertuzumab first administrated (loading dose) at 840 mg by intravenous infusion over 60 min then every 3 weeks at 420 mg by intravenous infusion over 30 to 90 min. Chemotherapy: * Paclitaxel administrated by intravenous infusion at 90 mg/m2 on day 1, 8, and 15 every 4 weeks for ≥4 months. OR * Vinorelbine first administrated by intravenous infusion at 25 mg/m2 on day 1, 8 then by intravenous infusion at 30 mg/m2 on day 1, 8, and 15 every 3 weeks for ≥4 months. Patients with hormone receptor-positive disease should have received endocrine therapy. Treatment was to be prescribed according to the current guidelines.
    Reporting group title
    T-DM1
    Reporting group description
    		 Following disease progression under 1st_line treatment, T-DM1 was administrated every 3 weeks until unacceptable toxicity or disease progression at the dose of 3.6 mg/kg by intravenous infusion.

    Primary: Overall survival at 24 months

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    End point title
    		 Overall survival at 24 months [1]
    End point description
    The primary objective of this trial was to evaluate the efficacy in terms of overall survival at 24 months of a chemotherapy-free dual HER2-inbibition with trastuzumab and pertuzumab (first-line) followed by T-DM1 (second-line) and of a chemotherapy-containing dual HER2-inhibition with trastuzumab and pertuzumab (first-line) followed by T-DM1 (second-line) in patients with HER2-positive metastatic breast cancer.
    End point type
    Primary
    End point timeframe
    Overall survival was defined as the amount of patients being alive at least 24 months after randomization.
    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: Statistical comparisons by hypothesis tests between treatment arms were not planned as the power would be very low.
    End point values
    		 Chemotherapy-free dual HER2-inbibition Chemotherapy-containing dual HER2-inbibition
    Number of subjects analysed
    105
    105
    Units: Percent of patients
        Alive
    79
    78
        Dead
    21
    22
    No statistical analyses for this end point

    Secondary: Progression-free survival of 1st-line treatment ignoring first CNS lesion

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    End point title
    		 Progression-free survival of 1st-line treatment ignoring first CNS lesion
    End point description
    Progression-free survival (PFS) of first-line treatment ignoring first central nervous system (CNS) lesion was the time from randomization to first event of disease progression (ignoring first CNS lesion event) or death of any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Tumor assessment were performed at baseline and after 8, 16, and 24 weeks, thereafter every 12 weeks during 1st-line treatment.
    End point values
    		 Chemotherapy-free dual HER2-inbibition Chemotherapy-containing dual HER2-inbibition
    Number of subjects analysed
    105
    105
    Units: month
        median (confidence interval 95%)
    8.4 (7.9 to 12.0)
    23.3 (18.9 to 33.1)
    No statistical analyses for this end point

    Secondary: PFS of second-line treatment

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    End point title
    		 PFS of second-line treatment
    End point description
    PFS of second-line treatment was defined as the time from registration to second-line treatment to the first event of disease progression during second-line treatment or death of any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Tumor assessment were performed within 3 weeks prior to second-line registration, after 9 and 18 weeks, then every 12 weeks.
    End point values
    		 T-DM1
    Number of subjects analysed
    111
    Units: month
        median (confidence interval 95%)
    6.9 (5.0 to 11.5)
    No statistical analyses for this end point

    Secondary: PFS of second-line treatment ignoring first CNS lesion

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    End point title
    		 PFS of second-line treatment ignoring first CNS lesion
    End point description
    PFS of second-line treatment was defined as the time from registration to second-line treatment to the first event of disease progression (ignoring CNS lesion) during second-line treatment or death of any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Tumor assessment were performed within 3 weeks prior to second-line registration, after 9 and 18 weeks, then every 12 weeks.
    End point values
    		 T-DM1
    Number of subjects analysed
    111
    Units: month
        median (confidence interval 95%)
    8.9 (5.3 to 11.7)
    No statistical analyses for this end point

    Secondary: Time to failure of strategy of first- plus second-line treatment

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    End point title
    		 Time to failure of strategy of first- plus second-line treatment
    End point description
    Time to failure of strategy (TFS) of first- plus second-line treatment was defined as the time from randomization to a TFS event of first- plus second-line treatment. A TFS event of first- plus second-line treatment was defined as disease rogression, CNS progression, or death of any cause, whichever occured first.
    End point type
    Secondary
    End point timeframe
    Tumor assessment were performed at baseline and after 8, 16, and 24 weeks, and every 12 weeks thereafter untill disease progression then within 3 weeks prior to second-line registration, after 9 and 18 weeks, then every 12 weeks.
    End point values
    		 Chemotherapy-free dual HER2-inbibition Chemotherapy-containing dual HER2-inbibition
    Number of subjects analysed
    105
    105
    Units: month
        median (confidence interval 95%)
    29.0 (18.9 to 63.4)
    48.6 (35.8 to 69.5)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    OS was defined as the time from randomization until death by any cause.
    End point values
    		 Chemotherapy-free dual HER2-inbibition Chemotherapy-containing dual HER2-inbibition
    Number of subjects analysed
    105
    105
    Units: month
        median (confidence interval 95%)
    60.5 (42.6 to 81)
    68.8 (55.3 to 75)
    No statistical analyses for this end point

    Secondary: Objective response of first-line treatment (based on investigator’s assessment)

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    End point title
    		 Objective response of first-line treatment (based on investigator’s assessment)
    End point description
    Objective response (OR) of first-line treatment was defined as the status complete response (CR) or partial response (PR) succeeded as best response during first-line of treatment.
    End point type
    Secondary
    End point timeframe
    Tumor assessment were performed at baseline and after 8, 16, and 24 weeks, thereafter every 12 weeks during 1st-line treatment.
    End point values
    		 Chemotherapy-free dual HER2-inbibition Chemotherapy-containing dual HER2-inbibition
    Number of subjects analysed
    105
    105
    Units: Percent of patients
        CR
    7
    25
        PR
    38
    36
    No statistical analyses for this end point

    Secondary: Disease control of first-line treatment (based on investigator’s assessment)

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    End point title
    		 Disease control of first-line treatment (based on investigator’s assessment)
    End point description
    Disease control (DC) of first-line treatment was defined as the status of response CR, PR or stable disease (SD) for a period of 6 months and no progressive disease (PD) at 6 months after randomization. Patients with SD and last evaluation before 6 months after randomization or no assessment within 6 months after randomization were not considered.
    End point type
    Secondary
    End point timeframe
    Tumor assessment were performed at baseline and after 8, 16, and 24 weeks, thereafter every 12 weeks during 1st-line treatment.
    End point values
    		 Chemotherapy-free dual HER2-inbibition Chemotherapy-containing dual HER2-inbibition
    Number of subjects analysed
    105
    105
    Units: Percent of patients
        CR
    7
    25
        PR
    38
    36
        SD ≥6 months
    17
    18
    No statistical analyses for this end point

    Secondary: OR of second-line treatment (based on investigator’s assessment)

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    End point title
    		 OR of second-line treatment (based on investigator’s assessment)
    End point description
    OR of second-line treatment was defined as the status of response CR or PR succeeded as best response during second-line of treatment.
    End point type
    Secondary
    End point timeframe
    Tumor assessment were performed within 3 weeks prior to second-line registration, after 9 and 18 weeks, then every 12 weeks.
    End point values
    		 T-DM1
    Number of subjects analysed
    111
    Units: Percent of patients
        CR
    8
        PR
    21
    No statistical analyses for this end point

    Secondary: DC of second-line treatment (based on investigator’s assessment)

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    End point title
    		 DC of second-line treatment (based on investigator’s assessment)
    End point description
    DC of second-line treatment was defined as the status of response CR, PR or SD for a period of 6 months and no PD at 6 months after registration of second-line treatment. Patients with SD and last evaluation before 6 months after registration to the second-line of treatment or no assessment within 6 months after registration to the second-line of treatment were not considered.
    End point type
    Secondary
    End point timeframe
    Tumor assessment were performed within 3 weeks prior to second-line registration, after 9 and 18 weeks, then every 12 weeks.
    End point values
    		 T-DM1
    Number of subjects analysed
    111
    Units: Percent of patients
        CR
    8
        PR
    21
        SD ≥6 months
    17
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From inclusion until 30 days after end of treatment (up to 7 years).
    Adverse event reporting additional description
    For non-serious adverse events, the number of occurrences were not recorded, the number of patient affected were the only value available. Thus, the number of patient affected was entered in both "Subjects affected number" and "Occurrence all number" fields.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Chemotherapy-free dual HER2-inbibition
    Reporting group description
    		 -

    Reporting group title
    Chemotherapy-containing dual HER2-inbibition
    Reporting group description
    		 -

    Reporting group title
    Second-line therapy
    Reporting group description
    		 -

    Serious adverse events
    		 Chemotherapy-free dual HER2-inbibition Chemotherapy-containing dual HER2-inbibition Second-line therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 105 (43.81%)
    37 / 103 (35.92%)
    38 / 111 (34.23%)
         number of deaths (all causes)
    33
    26
    39
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basalioma
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast angiosarcoma
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leiomyomas of the uterus
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (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
    Thromboembolic event
    Additional description: 1
         subjects affected / exposed
    1 / 105 (0.95%)
    1 / 103 (0.97%)
    0 / 111 (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
    Surgical and medical procedures
    Adnexectomy
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (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
    Breast conserving surgery with ALND
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hallux valgus requiring surgery
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (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
    Persistent exulceration of primary tumor requiring palliative ablation
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary lobectomy (L) with hilar and mediastinal adenectomy
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (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
    Spine surgery
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    2 / 105 (1.90%)
    1 / 103 (0.97%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurologic symptom
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reduced general condition
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 105 (0.95%)
    1 / 103 (0.97%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    4 / 105 (3.81%)
    0 / 103 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic organ prolapse
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 105 (0.95%)
    1 / 103 (0.97%)
    0 / 111 (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
    Thoracic pain
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (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
    Anxiety
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (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
    Confusion
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (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
    Investigations
    AST and ALT increased
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (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
    Ejection fraction decreased
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    3 / 111 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 105 (0.00%)
    2 / 103 (1.94%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (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
    Cranio-cerebral injury
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (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
    Fall
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (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
    Fracture
         subjects affected / exposed
    2 / 105 (1.90%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (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
    Incisional hernia
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (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
    Seroma
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertebral compression fracture
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (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
    Cardiac disorders
    3-vessel coronary disease
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    2 / 111 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (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
    Seizure
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Transient ischemic attacks
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 105 (0.00%)
    3 / 103 (2.91%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast infection
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic nerve disorder
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 105 (1.90%)
    4 / 103 (3.88%)
    2 / 111 (1.80%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 105 (1.90%)
    1 / 103 (0.97%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (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
    Back pain
         subjects affected / exposed
    1 / 105 (0.95%)
    1 / 103 (0.97%)
    0 / 111 (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
    Bone pain
         subjects affected / exposed
    1 / 105 (0.95%)
    1 / 103 (0.97%)
    0 / 111 (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
    Muscle cramps generalized
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (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
    Pathologic bone fracture
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 lung infection
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter-related infection
         subjects affected / exposed
    1 / 105 (0.95%)
    1 / 103 (0.97%)
    0 / 111 (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
    Dyspnoea
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis infective
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    1 / 105 (0.95%)
    1 / 103 (0.97%)
    0 / 111 (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
    Kidney infection
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 111 (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
    Lung infection
         subjects affected / exposed
    1 / 105 (0.95%)
    2 / 103 (1.94%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Purulent pleurisy
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 105 (0.95%)
    1 / 103 (0.97%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylodiscitis
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    12 / 111 (10.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vulval infection
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 105 (0.00%)
    2 / 103 (1.94%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Chemotherapy-free dual HER2-inbibition Chemotherapy-containing dual HER2-inbibition Second-line therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 105 (100.00%)
    103 / 103 (100.00%)
    111 / 111 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    6 / 105 (5.71%)
    3 / 103 (2.91%)
    4 / 111 (3.60%)
         occurrences all number
    6
    3
    4
    Vascular disorders
    Haematoma
         subjects affected / exposed
    4 / 105 (3.81%)
    7 / 103 (6.80%)
    2 / 111 (1.80%)
         occurrences all number
    4
    7
    2
    Hot flush
         subjects affected / exposed
    19 / 105 (18.10%)
    10 / 103 (9.71%)
    13 / 111 (11.71%)
         occurrences all number
    19
    10
    13
    Hypertension
         subjects affected / exposed
    100 / 105 (95.24%)
    102 / 103 (99.03%)
    104 / 111 (93.69%)
         occurrences all number
    100
    102
    104
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    8 / 105 (7.62%)
    7 / 103 (6.80%)
    7 / 111 (6.31%)
         occurrences all number
    8
    7
    7
    Oedema limbs
         subjects affected / exposed
    9 / 105 (8.57%)
    15 / 103 (14.56%)
    12 / 111 (10.81%)
         occurrences all number
    9
    15
    12
    Fatigue
         subjects affected / exposed
    60 / 105 (57.14%)
    81 / 103 (78.64%)
    79 / 111 (71.17%)
         occurrences all number
    60
    81
    79
    Fever
         subjects affected / exposed
    24 / 105 (22.86%)
    22 / 103 (21.36%)
    10 / 111 (9.01%)
         occurrences all number
    24
    22
    10
    Flu like symptoms
         subjects affected / exposed
    18 / 105 (17.14%)
    14 / 103 (13.59%)
    10 / 111 (9.01%)
         occurrences all number
    18
    14
    10
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 105 (2.86%)
    9 / 103 (8.74%)
    3 / 111 (2.70%)
         occurrences all number
    3
    9
    3
    Pain
         subjects affected / exposed
    22 / 105 (20.95%)
    32 / 103 (31.07%)
    18 / 111 (16.22%)
         occurrences all number
    22
    32
    18
    Pharyngitis
         subjects affected / exposed
    4 / 105 (3.81%)
    10 / 103 (9.71%)
    2 / 111 (1.80%)
         occurrences all number
    4
    10
    2
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    15 / 105 (14.29%)
    10 / 103 (9.71%)
    3 / 111 (2.70%)
         occurrences all number
    15
    10
    3
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    4 / 105 (3.81%)
    6 / 103 (5.83%)
    6 / 111 (5.41%)
         occurrences all number
    4
    6
    6
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis
         subjects affected / exposed
    11 / 105 (10.48%)
    16 / 103 (15.53%)
    8 / 111 (7.21%)
         occurrences all number
    11
    16
    8
    Cough
         subjects affected / exposed
    22 / 105 (20.95%)
    23 / 103 (22.33%)
    19 / 111 (17.12%)
         occurrences all number
    22
    23
    19
    Dyspnoea
         subjects affected / exposed
    34 / 105 (32.38%)
    23 / 103 (22.33%)
    27 / 111 (24.32%)
         occurrences all number
    34
    23
    27
    Epistaxis
         subjects affected / exposed
    16 / 105 (15.24%)
    24 / 103 (23.30%)
    19 / 111 (17.12%)
         occurrences all number
    16
    24
    19
    Voice alteration
         subjects affected / exposed
    4 / 105 (3.81%)
    7 / 103 (6.80%)
    1 / 111 (0.90%)
         occurrences all number
    4
    7
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    9 / 105 (8.57%)
    7 / 103 (6.80%)
    7 / 111 (6.31%)
         occurrences all number
    9
    7
    7
    Depression
         subjects affected / exposed
    7 / 105 (6.67%)
    14 / 103 (13.59%)
    11 / 111 (9.91%)
         occurrences all number
    7
    14
    11
    Insomnia
         subjects affected / exposed
    21 / 105 (20.00%)
    16 / 103 (15.53%)
    11 / 111 (9.91%)
         occurrences all number
    21
    16
    11
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    41 / 105 (39.05%)
    66 / 103 (64.08%)
    76 / 111 (68.47%)
         occurrences all number
    41
    66
    76
    Blood alkaline phosphatase increased
         subjects affected / exposed
    52 / 105 (49.52%)
    54 / 103 (52.43%)
    64 / 111 (57.66%)
         occurrences all number
    52
    54
    64
    Aspartate aminotransferase increased
         subjects affected / exposed
    53 / 105 (50.48%)
    66 / 103 (64.08%)
    96 / 111 (86.49%)
         occurrences all number
    53
    66
    96
    Blood bilirubin increased
         subjects affected / exposed
    13 / 105 (12.38%)
    11 / 103 (10.68%)
    17 / 111 (15.32%)
         occurrences all number
    13
    11
    17
    Creatinine urine increased
         subjects affected / exposed
    34 / 105 (32.38%)
    34 / 103 (33.01%)
    30 / 111 (27.03%)
         occurrences all number
    34
    34
    30
    Ejection fraction decreased
         subjects affected / exposed
    10 / 105 (9.52%)
    8 / 103 (7.77%)
    1 / 111 (0.90%)
         occurrences all number
    10
    8
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 105 (5.71%)
    7 / 103 (6.80%)
    16 / 111 (14.41%)
         occurrences all number
    6
    7
    16
    Lymphocyte count decreased
         subjects affected / exposed
    7 / 105 (6.67%)
    6 / 103 (5.83%)
    4 / 111 (3.60%)
         occurrences all number
    7
    6
    4
    Neutrophil count decreased
         subjects affected / exposed
    19 / 105 (18.10%)
    59 / 103 (57.28%)
    28 / 111 (25.23%)
         occurrences all number
    19
    59
    28
    Platelet count decreased
         subjects affected / exposed
    15 / 105 (14.29%)
    25 / 103 (24.27%)
    76 / 111 (68.47%)
         occurrences all number
    15
    25
    76
    Weight gain
         subjects affected / exposed
    33 / 105 (31.43%)
    32 / 103 (31.07%)
    19 / 111 (17.12%)
         occurrences all number
    33
    32
    19
    Weight loss
         subjects affected / exposed
    38 / 105 (36.19%)
    58 / 103 (56.31%)
    54 / 111 (48.65%)
         occurrences all number
    38
    58
    54
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    2 / 105 (1.90%)
    6 / 103 (5.83%)
    2 / 111 (1.80%)
         occurrences all number
    2
    6
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 105 (9.52%)
    16 / 103 (15.53%)
    6 / 111 (5.41%)
         occurrences all number
    10
    16
    6
    Dysesthesia
         subjects affected / exposed
    5 / 105 (4.76%)
    11 / 103 (10.68%)
    9 / 111 (8.11%)
         occurrences all number
    5
    11
    9
    Dysgeusia
         subjects affected / exposed
    15 / 105 (14.29%)
    20 / 103 (19.42%)
    10 / 111 (9.01%)
         occurrences all number
    15
    20
    10
    Headache
         subjects affected / exposed
    25 / 105 (23.81%)
    31 / 103 (30.10%)
    21 / 111 (18.92%)
         occurrences all number
    25
    31
    21
    Paraesthesia
         subjects affected / exposed
    13 / 105 (12.38%)
    34 / 103 (33.01%)
    16 / 111 (14.41%)
         occurrences all number
    13
    34
    16
    Peripheral motor neuropathy
         subjects affected / exposed
    2 / 105 (1.90%)
    5 / 103 (4.85%)
    7 / 111 (6.31%)
         occurrences all number
    2
    5
    7
    Peripheral sensory neuropathy
         subjects affected / exposed
    14 / 105 (13.33%)
    36 / 103 (34.95%)
    24 / 111 (21.62%)
         occurrences all number
    14
    36
    24
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    48 / 105 (45.71%)
    86 / 103 (83.50%)
    69 / 111 (62.16%)
         occurrences all number
    48
    86
    69
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    10 / 105 (9.52%)
    10 / 103 (9.71%)
    8 / 111 (7.21%)
         occurrences all number
    10
    10
    8
    Eye disorders
    Blurred vision
         subjects affected / exposed
    2 / 105 (1.90%)
    7 / 103 (6.80%)
    2 / 111 (1.80%)
         occurrences all number
    2
    7
    2
    Dry eye
         subjects affected / exposed
    9 / 105 (8.57%)
    9 / 103 (8.74%)
    8 / 111 (7.21%)
         occurrences all number
    9
    9
    8
    Watering eyes
         subjects affected / exposed
    5 / 105 (4.76%)
    11 / 103 (10.68%)
    9 / 111 (8.11%)
         occurrences all number
    5
    11
    9
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    18 / 105 (17.14%)
    24 / 103 (23.30%)
    11 / 111 (9.91%)
         occurrences all number
    18
    24
    11
    Constipation
         subjects affected / exposed
    15 / 105 (14.29%)
    29 / 103 (28.16%)
    26 / 111 (23.42%)
         occurrences all number
    15
    29
    26
    Diarrhoea
         subjects affected / exposed
    60 / 105 (57.14%)
    77 / 103 (74.76%)
    26 / 111 (23.42%)
         occurrences all number
    60
    77
    26
    Dry mouth
         subjects affected / exposed
    3 / 105 (2.86%)
    3 / 103 (2.91%)
    11 / 111 (9.91%)
         occurrences all number
    3
    3
    11
    Dyspepsia
         subjects affected / exposed
    8 / 105 (7.62%)
    14 / 103 (13.59%)
    7 / 111 (6.31%)
         occurrences all number
    8
    14
    7
    Dysphagia
         subjects affected / exposed
    8 / 105 (7.62%)
    6 / 103 (5.83%)
    2 / 111 (1.80%)
         occurrences all number
    8
    6
    2
    Gastritis
         subjects affected / exposed
    6 / 105 (5.71%)
    8 / 103 (7.77%)
    4 / 111 (3.60%)
         occurrences all number
    6
    8
    4
    Gastroesophageal reflux disease
         subjects affected / exposed
    10 / 105 (9.52%)
    10 / 103 (9.71%)
    7 / 111 (6.31%)
         occurrences all number
    10
    10
    7
    Haemorrhoids
         subjects affected / exposed
    5 / 105 (4.76%)
    6 / 103 (5.83%)
    2 / 111 (1.80%)
         occurrences all number
    5
    6
    2
    Mucositis oral
         subjects affected / exposed
    12 / 105 (11.43%)
    30 / 103 (29.13%)
    9 / 111 (8.11%)
         occurrences all number
    12
    30
    9
    Nausea
         subjects affected / exposed
    34 / 105 (32.38%)
    42 / 103 (40.78%)
    39 / 111 (35.14%)
         occurrences all number
    34
    42
    39
    Vomiting
         subjects affected / exposed
    12 / 105 (11.43%)
    16 / 103 (15.53%)
    8 / 111 (7.21%)
         occurrences all number
    12
    16
    8
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    8 / 105 (7.62%)
    36 / 103 (34.95%)
    12 / 111 (10.81%)
         occurrences all number
    8
    36
    12
    Dry skin
         subjects affected / exposed
    16 / 105 (15.24%)
    26 / 103 (25.24%)
    13 / 111 (11.71%)
         occurrences all number
    16
    26
    13
    Erythema
         subjects affected / exposed
    7 / 105 (6.67%)
    5 / 103 (4.85%)
    6 / 111 (5.41%)
         occurrences all number
    7
    5
    6
    Nail loss
         subjects affected / exposed
    5 / 105 (4.76%)
    11 / 103 (10.68%)
    5 / 111 (4.50%)
         occurrences all number
    5
    11
    5
    Pruritus
         subjects affected / exposed
    15 / 105 (14.29%)
    25 / 103 (24.27%)
    10 / 111 (9.01%)
         occurrences all number
    15
    25
    10
    Rash acneiform
         subjects affected / exposed
    11 / 105 (10.48%)
    23 / 103 (22.33%)
    3 / 111 (2.70%)
         occurrences all number
    11
    23
    3
    Rash maculo-papular
         subjects affected / exposed
    11 / 105 (10.48%)
    13 / 103 (12.62%)
    5 / 111 (4.50%)
         occurrences all number
    11
    13
    5
    Endocrine disorders
    Conjunctivitis
         subjects affected / exposed
    8 / 105 (7.62%)
    10 / 103 (9.71%)
    9 / 111 (8.11%)
         occurrences all number
    8
    10
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    16 / 105 (15.24%)
    25 / 103 (24.27%)
    16 / 111 (14.41%)
         occurrences all number
    16
    25
    16
    Back pain
         subjects affected / exposed
    17 / 105 (16.19%)
    16 / 103 (15.53%)
    20 / 111 (18.02%)
         occurrences all number
    17
    16
    20
    Bone pain
         subjects affected / exposed
    15 / 105 (14.29%)
    16 / 103 (15.53%)
    16 / 111 (14.41%)
         occurrences all number
    15
    16
    16
    Flank pain
         subjects affected / exposed
    3 / 105 (2.86%)
    6 / 103 (5.83%)
    3 / 111 (2.70%)
         occurrences all number
    3
    6
    3
    Myalgia
         subjects affected / exposed
    14 / 105 (13.33%)
    26 / 103 (25.24%)
    15 / 111 (13.51%)
         occurrences all number
    14
    26
    15
    Neck pain
         subjects affected / exposed
    7 / 105 (6.67%)
    9 / 103 (8.74%)
    2 / 111 (1.80%)
         occurrences all number
    7
    9
    2
    Cramp
         subjects affected / exposed
    9 / 105 (8.57%)
    24 / 103 (23.30%)
    8 / 111 (7.21%)
         occurrences all number
    9
    24
    8
    Pain in extremity
         subjects affected / exposed
    11 / 105 (10.48%)
    16 / 103 (15.53%)
    12 / 111 (10.81%)
         occurrences all number
    11
    16
    12
    Infections and infestations
    Bladder infection
         subjects affected / exposed
    2 / 105 (1.90%)
    8 / 103 (7.77%)
    1 / 111 (0.90%)
         occurrences all number
    2
    8
    1
    Bronchial infection
         subjects affected / exposed
    9 / 105 (8.57%)
    3 / 103 (2.91%)
    3 / 111 (2.70%)
         occurrences all number
    9
    3
    3
    Paronychia
         subjects affected / exposed
    1 / 105 (0.95%)
    9 / 103 (8.74%)
    2 / 111 (1.80%)
         occurrences all number
    1
    9
    2
    Rhinitis infective
         subjects affected / exposed
    11 / 105 (10.48%)
    11 / 103 (10.68%)
    3 / 111 (2.70%)
         occurrences all number
    11
    11
    3
    Skin infection
         subjects affected / exposed
    9 / 105 (8.57%)
    11 / 103 (10.68%)
    4 / 111 (3.60%)
         occurrences all number
    9
    11
    4
    Upper respiratory infection
         subjects affected / exposed
    12 / 105 (11.43%)
    14 / 103 (13.59%)
    9 / 111 (8.11%)
         occurrences all number
    12
    14
    9
    Urinary tract infection
         subjects affected / exposed
    5 / 105 (4.76%)
    17 / 103 (16.50%)
    5 / 111 (4.50%)
         occurrences all number
    5
    17
    5
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    27 / 105 (25.71%)
    19 / 103 (18.45%)
    27 / 111 (24.32%)
         occurrences all number
    27
    19
    27
    Hypokalaemia
         subjects affected / exposed
    2 / 105 (1.90%)
    6 / 103 (5.83%)
    3 / 111 (2.70%)
         occurrences all number
    2
    6
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    A rather good prognosis population included with a greater proportion of patients with primary metastatic disease and less prior adjuvant/neoadjuvant pretreatment like anti-HER2 and endocrine therapy.
    For support, Contact us.
    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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