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    Clinical Trial Results:
    A Phase 2, Multicenter, Single-Arm Study of Trastuzumab Emtansine in Patients With HER2 IHC-Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Received At Least One Prior Chemotherapy Regimen

    Summary
    EudraCT number
    		 2014-001237-83
    Trial protocol
    		 DE   ES   IT   PL  
    Global end of trial date
    26 Jul 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    23 Aug 2019
    First version publication date
    09 Nov 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    BO29389
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02289833
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hoffmann-LaRoche
    Sponsor organisation address
    Grenzacherstrasse 124, CH, Basel, Basel, Switzerland, 4070
    Public contact
    Medical Communications, Hoffmann-LaRoche, +41 8008218590, genentech@druginfo.com
    Scientific contact
    Medical Communications, Hoffmann-LaRoche, +41 8008218590, genentech@druginfo.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
    Final
    Date of interim/final analysis
    26 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to evaluate the efficacy of single-agent trastuzumab emtansine in subjects with centrally confirmed human epidermal growth factor receptor (HER2) immunohistochemistry (IHC)-positive (IHC2+ or IHC3+) locally advanced or metastatic non-small cell lung cancer (NSCLC) who had received at least one prior chemotherapy regimen, as measured by confirmed objective response rate (ORR).
    Protection of trial subjects
    All subjects signed an informed consent form before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    49
    EEA total number of subjects
    29
    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)
    27
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects were screened centrally for HER2 status, using archived tumor specimens from previously collected tissue, if available.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort IHC2+
    Arm description
    		 Subjects with HER2 IHC2-positive (IHC 2+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab emtansine
    Investigational medicinal product code
    Other name
    Kadcyla, T-DM1
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab emtansine will be administered intravenously (IV) at a dose of 3.6 milligrams/kilogram (mg/kg) on Day 1 of every 21-day cycle until disease progression (as assessed by the investigator), unmanageable toxicity, or study termination by the sponsor, whichever occurs first.

    Arm title
    		 Cohort IHC3+
    Arm description
    		 Subjects with HER2 IHC3-positive (IHC 3+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab emtansine
    Investigational medicinal product code
    Other name
    Kadcyla, T-DM1
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab emtansine will be administered intravenously (IV) at a dose of 3.6 mg/kg on Day 1 of every 21-day cycle until disease progression (as assessed by the investigator), unmanageable toxicity, or study termination by the sponsor, whichever occurs first.

    Number of subjects in period 1
    		Cohort IHC2+ Cohort IHC3+
    Started
    29
    20
    Completed
    2
    3
    Not completed
    27
    17
         Death
    23
    16
         Study Discontinuation
    -
    1
         Lost to follow-up
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort IHC2+
    Reporting group description
    		 Subjects with HER2 IHC2-positive (IHC 2+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine.

    Reporting group title
    Cohort IHC3+
    Reporting group description
    		 Subjects with HER2 IHC3-positive (IHC 3+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine.

    Reporting group values
    		 Cohort IHC2+ Cohort IHC3+ Total
    Number of subjects
    		 29 20 49
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.1 ( 10.3 ) 61.4 ( 8.6 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 13 7 20
        Male
    		 16 13 29

    End points

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    End points reporting groups
    Reporting group title
    Cohort IHC2+
    Reporting group description
    		 Subjects with HER2 IHC2-positive (IHC 2+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine.

    Reporting group title
    Cohort IHC3+
    Reporting group description
    		 Subjects with HER2 IHC3-positive (IHC 3+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine.

    Subject analysis set title
    PK Analyses for Trastuzumab Emtansine and Total Trastuzumab
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with HER2 IHC2 or IHC3-positive (IHC 2+ or IHC 3+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine. There were 47 patiens in PK pop from which 44 had valid sparse PK data.

    Subject analysis set title
    Cmax Analysis for DM1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with HER2 IHC2 or IHC3-positive (IHC 2+ or IHC 3+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine.

    Subject analysis set title
    Anti-drug Antibody Analysis Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with HER2 IHC2 or IHC3-positive (IHC 2+ or IHC 3+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine. Treated subjects with post-dose sample available for ADA analysis.

    Primary: Percentage of Subjects With Objective Response as per Investigator Assessment According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v. 1.1)

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    End point title
    		 Percentage of Subjects With Objective Response as per Investigator Assessment According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v. 1.1) [1]
    End point description
    Objective response is defined as a complete response (CR) or partial response (PR) determined on two consecutive assessments ≥ 4 weeks apart, based on investigator assessment according to RECIST, Version 1.1. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 millimeters (mm). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. The efficacy-evaluable population included subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    From Day 1 to disease progression (PD) or death from any cause, up to the clinical cutoff date (approximately 22 months)
    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: There was no statistical analyses done for this endpoint.
    End point values
    		 Cohort IHC2+ Cohort IHC3+
    Number of subjects analysed
    29
    20
    Units: percentage of subjects
        number (confidence interval 95%)
    0 (0 to 11.9)
    20.0 (5.7 to 43.7)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from first study drug administration to death from any cause. The efficacy-evaluable population included subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From Day 1 to death from any cause, up to the study completion date (approximately 43 months)
    End point values
    		 Cohort IHC2+ Cohort IHC3+
    Number of subjects analysed
    29
    20
    Units: months
        median (confidence interval 95%)
    12.2 (3.8 to 23.6)
    13.7 (4.1 to 33.0)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) as per Investigator Assessment According to RECIST v. 1.1

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    End point title
    		 Progression-Free Survival (PFS) as per Investigator Assessment According to RECIST v. 1.1
    End point description
    PFS is defined as the time from first study drug administration to first documented disease progression, based on investigator assessment using RECIST, v1.1, or death from any cause during the study, whichever occurs first. Disease progression is defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. The efficacy-evaluable population included subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From Day 1 to PD or death from any cause, up to the study completion date (approximately 43 months)
    End point values
    		 Cohort IHC2+ Cohort IHC3+
    Number of subjects analysed
    29
    20
    Units: months
        median (confidence interval 95%)
    2.6 (1.4 to 2.8)
    2.7 (1.4 to 8.3)
    No statistical analyses for this end point

    Secondary: Duration of Objective Response (DOR) Assessed According to RECIST v1.1

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    End point title
    		 Duration of Objective Response (DOR) Assessed According to RECIST v1.1
    End point description
    DOR is defined as the time from the initial documentation of response (CR or PR using RECIST, v1.1) to documented disease progression or death from any cause during the study. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. Data are reported for subjects with response. 9999 = the upper limit confidence interval was not calculable due to the low number of participants with events.
    End point type
    Secondary
    End point timeframe
    From first documented objective response to PD or death from any cause, up to the study completion date (approximately 43 months)
    End point values
    		 Cohort IHC2+ Cohort IHC3+
    Number of subjects analysed
    0 [2]
    4
    Units: months
        median (confidence interval 95%)
    ( to )
    7.3 (2.9 to 9999)
    Notes
    [2] - No subjects had response.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Benefit as per Investigator Assessment According to RECIST, v1.1

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    End point title
    		 Percentage of Subjects With Clinical Benefit as per Investigator Assessment According to RECIST, v1.1
    End point description
    Clinical benefit is defined as having a CR or PR or stable disease (using RECIST, v1.1) at 6 months. Subjects with no post-baseline response assessment are considered as experiencing no clinical benefit. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Stable disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum while in the study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. The efficacy-evaluable population included subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From Day 1 to PD or death from any cause, up to the study completion date (approximately 43 months)
    End point values
    		 Cohort IHC2+ Cohort IHC3+
    Number of subjects analysed
    29
    20
    Units: percentage of subjects
        number (confidence interval 95%)
    6.9 (0.85 to 22.77)
    30.0 (11.89 to 54.28)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Adverse Events (AEs) and Serious AEs (SAEs)

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    End point title
    		 Percentage of Subjects With Adverse Events (AEs) and Serious AEs (SAEs)
    End point description
    An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, whether or not considered related to the study drug. A SAE is any experience that: results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically significant. The safety-evaluable population included subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From Day 1 to 30 days after last dose of study drug, up to the study completion date (approximately 43 months)
    End point values
    		 Cohort IHC2+ Cohort IHC3+
    Number of subjects analysed
    29
    20
    Units: percentage of subjects
    number (not applicable)
        AEs
    93.1
    95.0
        SAEs
    17.2
    25.0
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration (Cmax) for Trastuzumab Emtansine and Total Trastuzumab

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    End point title
    		 Maximum Observed Concentration (Cmax) for Trastuzumab Emtansine and Total Trastuzumab
    End point description
    Cmax is the 0-21 day maximum observed concentration of a drug and was measured in blood serum. The pharmacokinetic (PK) population included subjects who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable subjects.
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 2 days) and 30 minutes (min) after end of infusion (infusion length= 100 min or less) on Day 1 of Cycles 1 and 3 (one cycle=21 days); at treatment discontinuation/early termination, up to the clinical cutoff date (approximately 22 months)
    End point values
    		 PK Analyses for Trastuzumab Emtansine and Total Trastuzumab
    Number of subjects analysed
    44
    Units: micrograms per milliliter (ug/mL)
    arithmetic mean (standard deviation)
        Trastuzumab Emtansine
    78.7 ( 19.6 )
        Total Trastuzumab
    79.9 ( 21.3 )
    No statistical analyses for this end point

    Secondary: AUCinf for Trastuzumab Emtansine and Total Trastuzumab

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    End point title
    		 AUCinf for Trastuzumab Emtansine and Total Trastuzumab
    End point description
    AUC (from zero to infinity) represents the total drug exposure over time in blood serum. The pharmacokinetic (PK) population included subjects who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable participants who consented to intense sampling.
    End point type
    Secondary
    End point timeframe
    Pre-dose & 30 minutes (min) post-infusion (inf.) on Day (D) 1 of Cycles (C) 1 & 3; post- inf. on D 2, 3, 4 or 5, 8, & 15 of C1, & pre- inf. on D1 of C2 & D1 of C4 (C=21D; at treatment discontinuation/early termination, up to approx. 22 months
    End point values
    		 PK Analyses for Trastuzumab Emtansine and Total Trastuzumab
    Number of subjects analysed
    4 [3]
    Units: days times ug/mL
    arithmetic mean (standard deviation)
        Trastuzumab Emtansine
    324 ( 49.9 )
        Total Trastuzumab
    436 ( 83.4 )
    Notes
    [3] - 4 subjects had valid intense sampling data.
    No statistical analyses for this end point

    Secondary: Elimination Half-Life (t1/2) for Trastuzumab Emtansine and Total Trastuzumab

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    End point title
    		 Elimination Half-Life (t1/2) for Trastuzumab Emtansine and Total Trastuzumab
    End point description
    t1/2 is the time required for the drug serum concentration to be reduced to half. The pharmacokinetic (PK) population included subjects who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable participants who consented to intense sampling.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 30minutes (min) post-infusion (inf.) on Day (D) 1 of Cycles (C) 1 and 3; post- inf. on D2,3,4 or 5,8, and 15 of C 1, and pre- inf. on D1 of C2 and D1 of C4 (C=21 days); at treatment discontinuation/early termination, up to approx. 22 months
    End point values
    		 PK Analyses for Trastuzumab Emtansine and Total Trastuzumab
    Number of subjects analysed
    4 [4]
    Units: days
    arithmetic mean (standard deviation)
        Trastuzumab Emtansine
    3.2 ( 0.51 )
        Total Trastuzumab
    5.6 ( 1.14 )
    Notes
    [4] - 4 subjects had valid intense sampling data.
    No statistical analyses for this end point

    Secondary: Volume of Distribution (Vss) for Trastuzumab Emtansine and Total Trastuzumab

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    End point title
    		 Volume of Distribution (Vss) for Trastuzumab Emtansine and Total Trastuzumab
    End point description
    Vss is the volume of distribution of study drug at steady state. The pharmacokinetic (PK) population included subjects who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable participants who consented to intense sampling.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 30 minutes (min) post-infusion (inf.) on D1 of C1 and 3; post- inf. on D2, 3, 4 or 5, 8, and 15 of C1, and pre- inf. on D1 of C2 and D1 of C4 (C=21 days); at treatment discontinuation/early termination, up to approx. 22 months
    End point values
    		 PK Analyses for Trastuzumab Emtansine and Total Trastuzumab
    Number of subjects analysed
    4 [5]
    Units: milligrams per kilogram (mL/kg)
    arithmetic mean (standard deviation)
        Trastuzumab Emtansine
    51.1 ( 1.81 )
        Total Trastuzumab
    60.7 ( 4.23 )
    Notes
    [5] - 4 subjects had valid intense sampling data.
    No statistical analyses for this end point

    Secondary: Clearance (CL) for Trastuzumab Emtansine and Total Trastuzumab

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    End point title
    		 Clearance (CL) for Trastuzumab Emtansine and Total Trastuzumab
    End point description
    CL is a measure of the body’s elimination of a drug from blood serum over time. The pharmacokinetic (PK) population included subjects who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable participants who consented to intense sampling.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 30 minutes (min) post-infusion (inf.) on D1 of C1 and 3; post- inf. on D2, 3, 4 or 5, 8, and 15 of C1, and pre- inf. on D1 of C2 and D1 of C4 (C=21 days); at treatment discontinuation/early termination, up to approx. 22 months
    End point values
    		 PK Analyses for Trastuzumab Emtansine and Total Trastuzumab
    Number of subjects analysed
    4 [6]
    Units: mL/day/kg
    arithmetic mean (standard deviation)
        Trastuzumab Emtansine
    11.35 ( 1.99 )
        Total Trastuzumab
    8.54 ( 1.99 )
    Notes
    [6] - 4 subjects had valid intense sampling data.
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration (Cmax) for N2'- deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine (DM1)

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    End point title
    		 Maximum Observed Concentration (Cmax) for N2'- deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine (DM1)
    End point description
    Cmax is the maximum observed concentration of a drug and was measured in blood plasma. The pharmacokinetic (PK) population included subjects who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable subjects.
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 2 days) and 30 minutes (min) after end of infusion (infusion length= 100 min or less) on Day 1 of Cycle 1 (one cycle=21 days); at treatment discontinuation/early termination, up to the clinical cutoff date (approximately 22 months)
    End point values
    		 Cmax Analysis for DM1
    Number of subjects analysed
    34
    Units: nanograms per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    4.3 ( 3.36 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Treatment-Emergent Anti-Drug Antibodies (ADAs)

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Anti-Drug Antibodies (ADAs)
    End point description
    The presence of ADAs in blood serum is an indication of the body's immune response to a drug. The pharmacokinetic (PK) population included subjects who had received at least one dose of study treatment and had at least one serum or plasma concentration result available at clinical data cut-off. Data are reported for evaluable subjects.
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 2 days) on Day 1 of Cycles 1 and 3; at treatment discontinuation/early termination, up to the clinical cutoff date (approximately 22 months)
    End point values
    		 Anti-drug Antibody Analysis Group
    Number of subjects analysed
    39 [7]
    Units: percentage of subjects
    0
    Notes
    [7] - Treated subjects with post-dose sample available for ADA analysis.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Died

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    End point title
    		 Percentage of Subjects who Died
    End point description
    The efficacy-evaluable population included subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From Day 1 to death from any cause, up to the study completion date (approximately 43 months)
    End point values
    		 Cohort IHC2+ Cohort IHC3+
    Number of subjects analysed
    29
    20
    Units: percentage of subjects
        number (not applicable)
    79.3
    80.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with PFS Event of Disease Progression, as per Investigator Assessment According to RECIST v. 1.1, or Death

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    End point title
    		 Percentage of Subjects with PFS Event of Disease Progression, as per Investigator Assessment According to RECIST v. 1.1, or Death
    End point description
    PFS is defined as the time from first study drug administration to first documented disease progression, based on investigator assessment using RECIST, v1.1, or death from any cause during the study, whichever occurs first. Disease progression is defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. The efficacy-evaluable population included subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From Day 1 to PD or death from any cause, up to the study completion date (approximately 43 months)
    End point values
    		 Cohort IHC2+ Cohort IHC3+
    Number of subjects analysed
    29
    20
    Units: percentage of subjects
        number (not applicable)
    100
    95.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with DOR Event of Disease Progression, Assessed According to RECIST v1.1

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    End point title
    		 Percentage of Subjects with DOR Event of Disease Progression, Assessed According to RECIST v1.1
    End point description
    DOR is defined as the time from the initial documentation of response (CR or PR using RECIST, v1.1) to documented disease progression using RECIST v1.1 or death from any cause during the study. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. The efficacy-evaluable population included subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first documented objective response to PD or death from any cause, up to the study completion date (approximately 43 months)
    End point values
    		 Cohort IHC2+ Cohort IHC3+
    Number of subjects analysed
    0 [8]
    4
    Units: percentage of subjects
        number (not applicable)
    75.0
    Notes
    [8] - No subjects had response.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to study completion (approximately 43 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Cohort IHC3+
    Reporting group description
    		 Subjects with HER2 IHC3-positive (IHC 3+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine.

    Reporting group title
    Cohort IHC2+
    Reporting group description
    		 Subjects with HER2 IHC2-positive (IHC 2+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine.

    Serious adverse events
    		 Cohort IHC3+ Cohort IHC2+
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 20 (25.00%)
    5 / 29 (17.24%)
         number of deaths (all causes)
    16
    23
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort IHC3+ Cohort IHC2+
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 20 (95.00%)
    24 / 29 (82.76%)
    Vascular disorders
    Poor venous access
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 20 (20.00%)
    5 / 29 (17.24%)
         occurrences all number
    6
    6
    Fatigue
         subjects affected / exposed
    3 / 20 (15.00%)
    10 / 29 (34.48%)
         occurrences all number
    5
    13
    Chills
         subjects affected / exposed
    4 / 20 (20.00%)
    1 / 29 (3.45%)
         occurrences all number
    4
    1
    Pyrexia
         subjects affected / exposed
    3 / 20 (15.00%)
    4 / 29 (13.79%)
         occurrences all number
    3
    4
    Chest pain
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    3
    Malaise
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 29 (3.45%)
         occurrences all number
    3
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Oedema
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Mucosal Dryness
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 20 (15.00%)
    7 / 29 (24.14%)
         occurrences all number
    4
    10
    Dyspnoea
         subjects affected / exposed
    2 / 20 (10.00%)
    8 / 29 (27.59%)
         occurrences all number
    2
    9
    Epistaxis
         subjects affected / exposed
    4 / 20 (20.00%)
    0 / 29 (0.00%)
         occurrences all number
    9
    0
    Pleural effusion
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 29 (6.90%)
         occurrences all number
    2
    2
    Dysphonia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Nasal congestion
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 29 (3.45%)
         occurrences all number
    2
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Productive cough
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Pulmonary pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal Pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Depressive symptom
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 29 (0.00%)
         occurrences all number
    3
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 20 (15.00%)
    2 / 29 (6.90%)
         occurrences all number
    3
    2
    Platelet count decreased
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 29 (6.90%)
         occurrences all number
    2
    3
    Weight decreased
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 29 (10.34%)
         occurrences all number
    1
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    4 / 20 (20.00%)
    3 / 29 (10.34%)
         occurrences all number
    4
    3
    Skin Wound
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    1 / 20 (5.00%)
    4 / 29 (13.79%)
         occurrences all number
    2
    5
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 29 (10.34%)
         occurrences all number
    1
    4
    Cerebrovascular accident
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Paraesthesia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Sciatica
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 29 (3.45%)
         occurrences all number
    3
    1
    Leukocytosis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 20 (15.00%)
    6 / 29 (20.69%)
         occurrences all number
    6
    8
    Vomiting
         subjects affected / exposed
    2 / 20 (10.00%)
    3 / 29 (10.34%)
         occurrences all number
    4
    6
    Dry mouth
         subjects affected / exposed
    0 / 20 (0.00%)
    4 / 29 (13.79%)
         occurrences all number
    0
    4
    Constipation
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 29 (3.45%)
         occurrences all number
    3
    1
    Diarrhoea
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 29 (6.90%)
         occurrences all number
    2
    2
    Dyspepsia
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 29 (3.45%)
         occurrences all number
    2
    1
    Abdominal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Stomatitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Odynophagia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 29 (6.90%)
         occurrences all number
    3
    2
    Rash maculo-papular
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 29 (0.00%)
         occurrences all number
    3
    0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Eczema
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Petechiae
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Alopecia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Onychoclasis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 20 (20.00%)
    4 / 29 (13.79%)
         occurrences all number
    6
    4
    Muscle spasms
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 29 (3.45%)
         occurrences all number
    2
    1
    Muscular weakness
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Myalgia
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Bone Pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Pain in Extremity
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    0
    4
    Urinary tract infection
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 29 (3.45%)
         occurrences all number
    7
    3
    Pneumonia
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Paronychia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 20 (15.00%)
    10 / 29 (34.48%)
         occurrences all number
    3
    10
    Hypokalaemia
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 29 (6.90%)
         occurrences all number
    2
    2
    Hypomagnesaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Iron Deficiency
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2

    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.
    None reported
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