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    Clinical Trial Results:
    A Phase IIIb, Single Arm Study of Carboplatin or Cisplatin Plus Etoposide with Atezolizumab (Anti-PD-L1 Antibody) in Patients with Untreated Extensive-Stage Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2019-002784-10
    Trial protocol
    		 ES  
    Global end of trial date
    14 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Dec 2023
    First version publication date
    14 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML41599
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Roche Farma S.A. (Soc. Unipersonal)
    Sponsor organisation address
    C/Ribera del Lora 50, Madrid, Spain, 28042
    Public contact
    Roche Farma S.A. (Soc. Unipersonal), Roche Farma S.A. (Soc. Unipersonal), 34 913253700, spain.start_up_unit@roche.com
    Scientific contact
    Roche Farma S.A. (Soc. Unipersonal), Roche Farma S.A. (Soc. Unipersonal), 34 913253700, spain.start_up_unit@roche.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
    14 Dec 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study is being conducted to evaluate the safety of atezolizumab + carboplatin or cisplatin + etoposide as first-line treatment for extensive-stage small cell lung cancer.
    Protection of trial subjects
    All study subjects were required to read and sign and Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Dec 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 155
    Worldwide total number of subjects
    155
    EEA total number of subjects
    155
    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)
    73
    From 65 to 84 years
    81
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 29 centers in one country.

    Pre-assignment
    Screening details
    		 A total of 155 participants were enrolled at 29 centers.

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

    Arms
    Arm title
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Arm description
    		 Participants will receive the following treatment regimen: atezolizumab + cisplatin/carboplatin + etoposide. Induction treatment will be administered on a 21-day cycle for four or six cycles (according to investigator's choice). Following the induction phase, participants will continue maintenance therapy with atezolizumab. Participants will be treated until loss of clinical benefit, or unaccepted toxicity, or withdrawal of consent, or death (whichever occurs first).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab will be administered by intravenous infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin will be administered as intravenous infusion at a dose of area under the concentration-time curve (AUC) of 5 mg/mL/min on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4).

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide will be administered intravenously at a dose of 100 mg/m^2 on Days 1, 2 and 3 of each 21-day cycle during the induction phase (Cycles 1-4).

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin will be administered as intravenous infusion at a dose of 75 mg per meter squared (75 mg/m^2) after completion of atezolizumab on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4).

    Number of subjects in period 1
    		Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Started
    155
    Completed
    0
    Not completed
    155
         Death
    128
         Withdrawal by Subject
    1
         Study Terminated by Sponsor
    22
         Lost to follow-up
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Reporting group description
    		 Participants will receive the following treatment regimen: atezolizumab + cisplatin/carboplatin + etoposide. Induction treatment will be administered on a 21-day cycle for four or six cycles (according to investigator's choice). Following the induction phase, participants will continue maintenance therapy with atezolizumab. Participants will be treated until loss of clinical benefit, or unaccepted toxicity, or withdrawal of consent, or death (whichever occurs first).

    Reporting group values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide Total
    Number of subjects
    		 155 155
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 73 73
        From 65-84 years
    		 81 81
        85 years and over
    		 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.67 ± 8.87 -
    Gender categorical
    Units: Subjects
        Female
    		 43 43
        Male
    		 112 112
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 14 14
        Not Hispanic or Latino
    		 140 140
        Not Reported
    		 1 1
        Unknown
    		 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 0 0
        Black or African American
    		 0 0
        Native Hawaiian or Pacific Islander
    		 0 0
        White
    		 154 154
        Unknown
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Reporting group description
    		 Participants will receive the following treatment regimen: atezolizumab + cisplatin/carboplatin + etoposide. Induction treatment will be administered on a 21-day cycle for four or six cycles (according to investigator's choice). Following the induction phase, participants will continue maintenance therapy with atezolizumab. Participants will be treated until loss of clinical benefit, or unaccepted toxicity, or withdrawal of consent, or death (whichever occurs first).

    Primary: Mean Number of Cycles of Carboplatin or Cisplatin

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    End point title
    		 Mean Number of Cycles of Carboplatin or Cisplatin [1]
    End point description
    There is 4 or 6 cycles of carboplatin or cisplatin. Each cycle is 21 days. A participant can have cycles of carboplatin and cisplatin during induction phase.
    End point type
    Primary
    End point timeframe
    From Baseline up to 18 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: Cycle
        arithmetic mean (standard deviation)
    4.49 ± 1.40
    No statistical analyses for this end point

    Primary: Mean Number of Cycles of Atezolizumab (Both Induction and Maintenance Phases)

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    End point title
    		 Mean Number of Cycles of Atezolizumab (Both Induction and Maintenance Phases) [2]
    End point description
    The induction phase of the study will consist of four or six cycles of atezolizumab plus chemotherapy, with each cycle being 21 days in duration. After the induction phase, patients will begin maintenance therapy with atezolizumab every 3 weeks.
    End point type
    Primary
    End point timeframe
    Baseline up to 36 months
    Notes
    [2] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: Cycles
        arithmetic mean (standard deviation)
    11.39 ± 9.47
    No statistical analyses for this end point

    Primary: Mean Treatment Duration of Atezolizumab

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    End point title
    		 Mean Treatment Duration of Atezolizumab [3]
    End point description
    Treatment duration is defined as the total number of days from first treatment administration to the last treatment administration +1.
    End point type
    Primary
    End point timeframe
    Baseline up to approximately 36 months
    Notes
    [3] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: Days
        arithmetic mean (standard deviation)
    242.10 ± 214.66
    No statistical analyses for this end point

    Primary: Percentage of Participants with Dose Interruption

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    End point title
    		 Percentage of Participants with Dose Interruption [4]
    End point description
    End point type
    Primary
    End point timeframe
    From baseline up to 36 months
    Notes
    [4] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: percentage of participants
    number (not applicable)
        Yes
    78.06
        No
    21.94
    No statistical analyses for this end point

    Primary: Mean Number of Cycles of Etoposide

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    End point title
    		 Mean Number of Cycles of Etoposide [5]
    End point description
    There is 4 or 6 cycles of etoposide. Each cycle is 21 days.
    End point type
    Primary
    End point timeframe
    From baseline up to 18 months
    Notes
    [5] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: Cycle
        arithmetic mean (standard deviation)
    4.57 ± 1.35
    No statistical analyses for this end point

    Primary: Percentage of Participants with Transient or Permanent Dose Interruption

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    End point title
    		 Percentage of Participants with Transient or Permanent Dose Interruption [6]
    End point description
    A participant can be counted in several categories.
    End point type
    Primary
    End point timeframe
    From baseline to 36 months
    Notes
    [6] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    121
    Units: Percentage of Participants
    number (not applicable)
        Transient
    91.74
        Permanent
    21.49
    No statistical analyses for this end point

    Primary: Percentage of Participants Receiving Cycles of Chemotherapy

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    End point title
    		 Percentage of Participants Receiving Cycles of Chemotherapy [7]
    End point description
    The cycles range from less than 4 cycles to 6 cycles. Each cycle is 21 days.
    End point type
    Primary
    End point timeframe
    From Baseline to 18 months
    Notes
    [7] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: Percentage of Participants
    number (not applicable)
        Less than 4 cycles
    9.68
        4 cycles
    49.03
        5 cycles
    2.58
        6 cycles
    38.71
    No statistical analyses for this end point

    Primary: Percentage of Participants with Treatment Emergent AEs Leading to Study Drug Discontinuation or Interruption by Primary System Organ Class

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    End point title
    		 Percentage of Participants with Treatment Emergent AEs Leading to Study Drug Discontinuation or Interruption by Primary System Organ Class [8]
    End point description
    Treatment-emergent AE (TEAE) is defined as an AE that began after the start of trial medication treatment. The dictionary used was MedDRA v25.1
    End point type
    Primary
    End point timeframe
    From baseline up to 36 months
    Notes
    [8] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: Percentage of Participants
    number (not applicable)
        Any Class
    76.77
        Blood and Lymphatic System Disorders
    34.19
        Investigations
    21.29
        General Disorders and Admin Site Conditions
    14.84
        Infections and Infestations
    14.84
        Gastrointestinal Disorders
    13.55
        Respiratory, Thoracic and Mediastinal Disorders
    9.03
        Nervous System Disorders
    7.10
        Metabolism and Nutrition Disorders
    6.45
        Endocrine Disorders
    4.52
        Renal and Urinary Disorders
    3.87
        Musculoskeletal and Connective Tissue Disorders
    3.23
        Psychiatric Disorders
    3.23
        Skin and Subcutaneous Tissue Disorders
    2.58
        Cardiac Disorders
    1.94
        Vascular Disorders
    1.94
        Eye Disorders
    0.65
        Hepatobiliary Disorders
    0.65
        Neoplasms Benign, Malignant and Unspecified
    0.65
        Social Circumstances
    0.65
    No statistical analyses for this end point

    Primary: Percentage of Participants Taking Concomitant Medications (Corticosteroids) by Anatomic Class

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    End point title
    		 Percentage of Participants Taking Concomitant Medications (Corticosteroids) by Anatomic Class [9]
    End point description
    Concomitant therapy includes any medication used by a patient from 7 days prior to screening until the treatment discontinuation visit. Participants with premedication are included in the table. A medication can be counted in several categories.
    End point type
    Primary
    End point timeframe
    From baseline up to 36 months
    Notes
    [9] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: Percentage of Participants
    number (not applicable)
        Any Concomitant Medications
    91.61
        Systemic Hormonal Preparations
    88.39
        Dermatologicals
    14.84
        Respiratory System
    10.32
        Alimentary Tract and Metabolism
    1.29
        Blood and Blood Forming Organs
    0.65
    No statistical analyses for this end point

    Primary: Percentage of Participants Taking Concomitant Medications by Anatomic Class

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    End point title
    		 Percentage of Participants Taking Concomitant Medications by Anatomic Class [10]
    End point description
    Concomitant therapy includes any medication used by a patient from 7 days prior to screening until the treatment discontinuation visit. Participants with premedication are included in the table. A medication can be counted in several categories.
    End point type
    Primary
    End point timeframe
    From baseline up to 36 months
    Notes
    [10] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: Percentage of Participants
    number (not applicable)
        Any Concomitant Medications
    100
        Alimentary Tract and Metabolism
    97.42
        Systemic Hormonal Preparations
    90.32
        Nervous System
    86.45
        Blood and Blood Forming Organs
    67.10
        Antineoplastic and Immunomodulating Agents
    59.35
        Antiinfectives for Systemic Use
    58.06
        Cardiovascular System
    54.84
        Respiratory System
    45.16
        Musculo-Skeletal System
    41.94
        Dermatologicals
    20.65
        Genito Urinary System & Sex Hormones
    10.97
        Sensory Organs
    7.74
        Various
    7.74
    No statistical analyses for this end point

    Primary: Kaplan-Meier Cumulative Incidence Probability of Treatment Emergent AEs of Special Interest During Treatment Period

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    End point title
    		 Kaplan-Meier Cumulative Incidence Probability of Treatment Emergent AEs of Special Interest During Treatment Period [11]
    End point description
    Out of 155 participants, 148 participants were censored and there were 7 events. Event is any patient who has experienced at least one treatment emergent AE of special interest during treatment period. Censor is any patient who has not experienced a treatment emergent AE of special interest during treatment period.
    End point type
    Primary
    End point timeframe
    From baseline to 36 months
    Notes
    [11] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: percentage
    number (confidence interval 95%)
        At 200 days
    1.58 (0.40 to 6.15)
        At 400 days
    6.01 (2.00 to 17.33)
        At 600 days
    16.45 (6.40 to 38.64)
        At 800 days
    23.41 (10.00 to 49.10)
        At 1000 days
    23.41 (10.00 to 49.10)
    No statistical analyses for this end point

    Primary: Percentage of Participants with Treatment Emergent AEs

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    End point title
    		 Percentage of Participants with Treatment Emergent AEs [12]
    End point description
    Percentage of participants with at least one treatment AE. Clopper-Pearson is used for 95% confidence interval.
    End point type
    Primary
    End point timeframe
    From baseline up to 36 months
    Notes
    [12] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: percentage of participants
    number (confidence interval 95%)
        Any Grade
    100 (97.6 to 100)
        Grade 1-2
    98.1 (94.4 to 99.6)
        Grade 3-4
    72.3 (64.5 to 79.1)
        Grade 5
    11.6 (7.0 to 17.7)
    No statistical analyses for this end point

    Primary: Percentage of Participants with Treatment Related AEs

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    End point title
    		 Percentage of Participants with Treatment Related AEs [13]
    End point description
    Percentage of participants with at least one treatment emergent AE. Clopper-Pearson is used for 95% confidence interval.
    End point type
    Primary
    End point timeframe
    From baseline up to 36 months
    Notes
    [13] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: percentage of participants
    number (confidence interval 95%)
        Any Grade
    74.2 (66.6 to 80.9)
        Grade 1-2
    68.4 (60.4 to 75.6)
        Grade 3-4
    27.7 (20.9 to 35.5)
        Grade 5
    0.6 (0.0 to 3.5)
    No statistical analyses for this end point

    Primary: Percentage of Participants with Treatment Related SAEs

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    End point title
    		 Percentage of Participants with Treatment Related SAEs [14]
    End point description
    Percentage of participants with at least one treatment emergent AE. Clopper-Pearson is used for 95% confidence interval.
    End point type
    Primary
    End point timeframe
    From baseline up to 36 months
    Notes
    [14] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: percentage of participants
    number (confidence interval 95%)
        Any Grade
    12.3 (7.5 to 18.5)
        Grade 1-2
    1.9 (0.4 to 5.6)
        Grade 3-4
    10.3 (6.0 to 16.2)
        Grade 5
    0.6 (0.0 to 3.5)
    No statistical analyses for this end point

    Primary: Mean Change in Diastolic Blood Pressure

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    End point title
    		 Mean Change in Diastolic Blood Pressure [15]
    End point description
    The mean changes are recorded at baseline, during and following study treatment administration.
    End point type
    Primary
    End point timeframe
    Baseline, Induction Phase(IP) Cycle(C) 1 pre- & post-dose, IPC2 pre- & post-dose, IPC3 pre- & post-dose, IPC4 pre- & post-dose, Maintenance Phase(MP) Visit(V) 1 pre- & post-dose, MPV2 pre- & post-dose, MPV3 pre- & post-dose, MPV4 pre- & post-dose
    Notes
    [15] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: mm Hg
    arithmetic mean (standard deviation)
        Baseline (n=155)
    75.17 ± 11.09
        IP Cycle 1 pre-dose (n=143)
    0.00 ± 0.00
        IP Cycle 1 post dose (n=93)
    -0.59 ± 8.96
        IP Cycle 2 pre-dose (n=144)
    -3.22 ± 9.79
        IP Cycle 2 post-dose (n=72)
    -2.61 ± 10.36
        IP Cycle 3 pre-dose (n=140)
    -2.76 ± 10.29
        IP Cycle 3 post-dose (n=69)
    -3.38 ± 9.16
        IP Cycle 4 pre-dose (n=134)
    -2.85 ± 10.72
        IP Cycle 4 post-dose (n=58)
    -2.28 ± 9.73
        MP Visit 1 pre-dose (n=124)
    -2.15 ± 10.90
        MP Visit 1 post-dose (n=55)
    -1.04 ± 11.61
        MP Visit 2 pre-dose (n=112)
    -1.35 ± 10.53
        MP Visit 2 post-dose (n=49)
    -1.84 ± 12.26
        MP Visit 3 pre-dose (n=91)
    -1.00 ± 10.77
        MP Visit 3 post-dose (n=44)
    0.25 ± 9.32
        MP Visit 4 pre-dose (n=74)
    -1.59 ± 11.14
        MP Visit 4 post-dose (n=35)
    1.83 ± 10.67
    No statistical analyses for this end point

    Primary: Percentage of Participants with Treatment Emergent AEs of Special Interest

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    End point title
    		 Percentage of Participants with Treatment Emergent AEs of Special Interest [16]
    End point description
    Percentage of participants with at least one treatment emergent AE of special interest. Clopper-Pearson is used for 95% confidence interval.
    End point type
    Primary
    End point timeframe
    from baseline up to 36 months
    Notes
    [16] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: percentage of participants
    number (confidence interval 95%)
        Any Grade
    4.5 (1.8 to 9.1)
        Grade 1-2
    2.6 (0.7 to 6.5)
        Grade 3-4
    1.3 (0.2 to 4.6)
        Grade 5
    0.6 (0.0 to 3.5)
    No statistical analyses for this end point

    Primary: Mean Change in Systolic Blood Pressure

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    End point title
    		 Mean Change in Systolic Blood Pressure [17]
    End point description
    The mean changes are recorded at baseline, during and following study treatment administration.
    End point type
    Primary
    End point timeframe
    Baseline, IPC1 pre- & post-dose, IPC2 pre- & post-dose, IPC3 pre- & post-dose, IPC4 pre- & post-dose, MPV1 pre- & post-dose, MPV2 pre- & post-dose, MPV3 pre- & post-dose, MPV4 pre- & post-dose
    Notes
    [17] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: mm Hg
    arithmetic mean (standard deviation)
        Baseline
    126.10 ± 17.03
        IP Cycle 1 pre-dose (n=143)
    0.00 ± 0.00
        IP Cycle 1 post-dose (n=93)
    1.24 ± 14.97
        IP Cycle 2 pre-dose (n=144)
    -4.69 ± 16.94
        IP Cycle 2 post-dose (n=72)
    -2.64 ± 16.16
        IP Cycle 3 pre-dose (n=140)
    -4.16 ± 16.89
        IP Cycle 3 post-dose (n=69)
    -2.35 ± 14.67
        IP Cycle 4 pre-dose (n=134)
    -3.12 ± 18.82
        IP Cycle 4 post-dose (n=58)
    0.00 ± 15.69
        MP Visit 1 pre-dose (n=124)
    -2.98 ± 20.00
        MP Visit 1 post-dose (n=55)
    1.04 ± 19.98
        MP Visit 2 pre-dose (n=112)
    -0.57 ± 23.17
        MP Visit 2 post-dose (n=49)
    -0.55 ± 23.17
        MP Visit 3 pre-dose (n=91)
    -1.07 ± 18.51
        MP Visit 3 post-dose (n=44)
    0.34 ± 15.07
        MP Visit 4 pre-dose (n=74)
    -0.81 ± 20.19
        MP Visit 4 post-dose (n=35)
    0.31 ± 18.47
    No statistical analyses for this end point

    Primary: Mean Change in Weight

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    End point title
    		 Mean Change in Weight [18]
    End point description
    The mean changes are recorded at baseline, during and following study treatment administration.
    End point type
    Primary
    End point timeframe
    Baseline, IPC1 pre- & post-dose, IPC2 pre- & post-dose, IPC3 pre- & post-dose, IPC4 pre- & post-dose, MPV1 pre- & post-dose, MPV2 pre- & post-dose, MPV3 pre- & post-dose, MPV4 pre- & post-dose
    Notes
    [18] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: kg
    arithmetic mean (standard deviation)
        Baseline (n=153)
    73.81 ± 14.82
        IP Cycle 1 pre dose (n=130)
    0.00 ± 0.00
        IP Cycle 1 post-dose (n=67)
    -0.02 ± 0.13
        IP Cycle 2 pre dose (n=135)
    -0.11 ± 4.15
        IP Cycle 2 post-dose (n=59)
    -0.52 ± 3.42
        IP Cycle 3 pre dose (n=134)
    -0.37 ± 3.34
        IP Cycle 3 post-dose (n=58)
    -0.20 ± 4.05
        IP Cycle 4 pre dose (n=131)
    0.21 ± 4.11
        IP Cycle 4 post-dose (n=51)
    0.33 ± 4.32
        MP Visit 1 pre-dose (n=122)
    1.17 ± 4.95
        MP Visit 1 post-dose (n=46)
    0.52 ± 4.42
        MP Visit 2 pre-dose (n=111)
    1.41 ± 5.62
        MP Visit 2 post-dose (n=38)
    0.89 ± 5.26
        MP Visit 3 pre-dose (n=90)
    2.17 ± 5.94
        MP Visit 3 post-dose (n=36)
    1.18 ± 6.73
        MP Visit 4 pre-dose (n=74)
    3.13 ± 6.05
        MP Visit 4 post-dose (n=28)
    1.19 ± 5.09
    No statistical analyses for this end point

    Primary: Mean Change in Pulse Rate

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    End point title
    		 Mean Change in Pulse Rate [19]
    End point description
    The mean changes are recorded at baseline, during and following study treatment administration.
    End point type
    Primary
    End point timeframe
    Baseline, IPC1 pre- & post-dose, IPC2 pre- & post-dose, IPC3 pre- & post-dose, IPC4 pre- & post-dose, MPV1 pre- & post-dose, MPV2 pre- & post-dose, MPV3 pre- & post-dose, MPV4 pre- & post-dose
    Notes
    [19] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: beats/min
    arithmetic mean (standard deviation)
        Baseline (n=155)
    84.12 ± 14.49
        IP Cycle 1 pre-dose (n=143)
    0.00 ± 0.00
        IP Cycle 1 post-dose (n=93)
    -3.08 ± 11.89
        IP Cycle 2 pre-dose (n=144)
    -2.55 ± 14.56
        IP Cycle 2 post-dose (n=72)
    -3.63 ± 16.06
        IP Cycle 3 pre-dose (n=140)
    -1.73 ± 13.87
        IP Cycle 3 post-dose (n=69)
    -4.07 ± 13.26
        IP Cycle 4 pre-dose (n=134)
    -3.14 ± 14.40
        IP Cycle 4 post-dose (n=58)
    -5.03 ± 14.64
        MP Visit 1 pre-dose (n=124)
    -1.77 ± 14.34
        MP Visit 1 post-dose (n=55)
    -3.38 ± 12.90
        MP Visit 2 pre-dose (n=112)
    -3.33 ± 13.04
        MP Visit 2 post-dose (n=47)
    -4.91 ± 14.11
        MP Visit 3 pre-dose (n=91)
    -2.46 ± 14.37
        MP Visit 3 post-dose (n=44)
    -4.16 ± 15.44
        MP Visit 4 pre-dose (n=74)
    -3.72 ± 13.94
        MP Visit 4 post-dose (n=34)
    -5.65 ± 16.11
    No statistical analyses for this end point

    Primary: Mean Change in Respiratory Rate

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    End point title
    		 Mean Change in Respiratory Rate [20]
    End point description
    The mean changes are recorded at baseline, during and following study treatment administration.
    End point type
    Primary
    End point timeframe
    Baseline, IPC1 pre- & post-dose, IPC2 pre- & post-dose, IPC3 pre- & post-dose, IPC4 pre- & post-dose, MPV1 pre- & post-dose, MPV2 pre- & post-dose, MPV3 pre- & post-dose, MPV4 pre- & post-dose
    Notes
    [20] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: breaths/min
    arithmetic mean (standard deviation)
        Baseline (n=149)
    17.04 ± 2.62
        IP Cycle 1 pre-dose (n=134)
    0.00 ± 0.00
        IP Cycle 1 post-dose (n=90)
    -0.37 ± 1.80
        IP Cycle 2 pre-dose (n=136)
    -0.25 ± 2.49
        IP Cycle 2 post-dose (n=72)
    -0.04 ± 2.17
        IP Cycle 3 pre-dose (n=131)
    -0.56 ± 2.58
        IP Cycle 3 post-dose (n=68)
    -0.47 ± 2.47
        IP Cycle 4 pre-dose (n=123)
    -0.52 ± 2.51
        IP Cycle 4 post-dose (n=58)
    -0.29 ± 2.23
        MP Visit 1 pre-dose (n=114)
    -0.31 ± 2.60
        MP Visit 1 post-dose (n=55)
    0.11 ± 2.07
        MP Visit 2 pre-dose (n=103)
    -0.21 ± 2.49
        MP Visit 2 post-dose (n=47)
    -0.38 ± 2.13
        MP Visit 3 pre-dose (n=88)
    -0.33 ± 2.21
        MP Visit 3 post-dose (n=43)
    -0.14 ± 2.10
        MP Visit 4 pre-dose (n=72)
    0.00 ± 2.05
        MP Visit 4 post-dose (n=33)
    -0.12 ± 1.19
    No statistical analyses for this end point

    Primary: Mean Change in Lymphocytes

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    End point title
    		 Mean Change in Lymphocytes [21]
    End point description
    The mean changes are recorded at baseline, during and following study treatment administration.
    End point type
    Primary
    End point timeframe
    Baseline, IP Cycle 2, IP Cycle 3, IP Cycle 4, MP Visit 1, MP Visit 2, MP Visit 3, MP Visit 4
    Notes
    [21] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: 10^9/L
    arithmetic mean (standard deviation)
        Baseline (n=155)
    1.62 ± 0.70
        IP Cycle 2 (n=145)
    0.37 ± 1.81
        IP Cycle 3 (n=139)
    0.25 ± 0.93
        IP Cycle 4 (n=139)
    0.14 ± 0.82
        MP Cycle 1 (n=131)
    0.24 ± 3.57
        MP Cycle 2 (n=117)
    -0.03 ± 0.76
        MP Cycle 3 (n=97)
    -0.07 ± 0.86
        MP Cycle 4 (n=78)
    -0.02 ± 0.94
    No statistical analyses for this end point

    Primary: Mean Change in Neutrophils

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    End point title
    		 Mean Change in Neutrophils [22]
    End point description
    The mean changes are recorded at baseline, during and following study treatment administration.
    End point type
    Primary
    End point timeframe
    Baseline, IP Cycle 2, IP Cycle 3, IP Cycle 4, MP Visit 1, MP Visit 2, MP Visit 3, MP Visit 4
    Notes
    [22] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: 10^9/L
    arithmetic mean (standard deviation)
        Baseline (n=155)
    7.26 ± 5.96
        IP Cycle 2 (n=144)
    -1.94 ± 6.99
        IP Cycle 3 (n=139)
    -2.74 ± 6.51
        IP Cycle 4 (n=139)
    -2.94 ± 7.53
        MP Cycle 1 (n=130)
    -3.02 ± 9.11
        MP Cycle 2 (n=117)
    -2.35 ± 6.67
        MP Cycle 3 (n=97)
    -2.78 ± 6.93
        MP Cycle 4 (=78)
    -2.88 ± 7.92
    No statistical analyses for this end point

    Primary: Mean Change in Platelets

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    End point title
    		 Mean Change in Platelets [23]
    End point description
    The mean changes are recorded at baseline, during and following study treatment administration.
    End point type
    Primary
    End point timeframe
    Baseline, IP Cycle 2, IP Cycle 3, IP Cycle 4, MP Visit 1, MP Visit 2, MP Visit 3, MP Visit 4
    Notes
    [23] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: 10^9/L
    arithmetic mean (standard deviation)
        Baseline (n=155)
    281.86 ± 97.99
        IP Cycle 2 (n=149)
    75.67 ± 139.58
        IP Cycle 3 (n=142)
    41.92 ± 138.54
        IP Cycle 4 (n=140)
    1.07 ± 117.87
        MP Cycle 1 (n=133)
    -48.47 ± 108.75
        MP Cycle 2 (n=117)
    -57.80 ± 78.91
        MP Cycle 3 (n=97)
    -70.39 ± 81.19
        MP Cycle 4 (n=78)
    -61.44 ± 89.35
    No statistical analyses for this end point

    Primary: Mean Change in Neutrophil-to-Lymphocyte Ratio

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    End point title
    		 Mean Change in Neutrophil-to-Lymphocyte Ratio [24]
    End point description
    The mean changes are recorded at baseline, during and following study treatment administration.
    End point type
    Primary
    End point timeframe
    Baseline, IP Cycle 2, IP Cycle 3, IP Cycle 4, MP Visit 1, MP Visit 2, MP Visit 3, MP Visit 4
    Notes
    [24] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: not applicable
    arithmetic mean (standard deviation)
        Baseline (n=155)
    5.40 ± 5.09
        IP Cycle 2 (n=144)
    -1.73 ± 5.33
        IP Cycle 3 (n=139)
    -2.30 ± 4.49
        IP Cycle 4 (n=139)
    -2.31 ± 5.10
        MP Cycle 1 (n=130)
    -2.00 ± 6.36
        MP Cycle 2 (n=117)
    -1.15 ± 5.04
        MP Cycle 3 (n=97)
    -1.42 ± 4.48
        MP Cycle 4 (n=78)
    -1.18 ± 5.86
    No statistical analyses for this end point

    Primary: Mean Change in Platelet-to-Lymphocyte Ratio

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    End point title
    		 Mean Change in Platelet-to-Lymphocyte Ratio [25]
    End point description
    The mean changes are recorded at baseline, during and following study treatment administration.
    End point type
    Primary
    End point timeframe
    Baseline, IP Cycle 2, IP Cycle 3, IP Cycle 4, MP Visit 1, MP Visit 2, MP Visit 3, MP Visit 4
    Notes
    [25] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: not applicable
    arithmetic mean (standard deviation)
        Baseline (n=155)
    206.94 ± 123.36
        IP Cycle 2 (n=145)
    22.14 ± 154.59
        IP Cycle 3 (n=139)
    -2.92 ± 132.91
        IP Cycle 4 (n=139)
    -17.92 ± 121.78
        MP Cycle 1 (n=131)
    -24.28 ± 128.33
        MP Cycle 2 (n=117)
    -30.32 ± 112.68
        MP Cycle 3 (n=97)
    -36.59 ± 104.34
        MP Cycle 4 (n=78)
    -27.38 ± 112.91
    No statistical analyses for this end point

    Primary: Mean Change to Lactate Dehydrogenase

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    End point title
    		 Mean Change to Lactate Dehydrogenase [26]
    End point description
    The mean changes are recorded at baseline, during and following study treatment administration.
    End point type
    Primary
    End point timeframe
    Baseline, IP Cycle 2, IP Cycle 3, IP Cycle 4, MP Visit 1, MP Visit 2, MP Visit 3, MP Visit 4
    Notes
    [26] - 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 analysis done for the outcome measure.
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: IU/L
    arithmetic mean (standard deviation)
        Baseline (n=150)
    397.31 ± 402.77
        IP Cycle 2 (n=133)
    -125.63 ± 331.98
        IP Cycle 3 (n=127)
    -139.38 ± 355.03
        IP Cycle 4 (n=131)
    -138.41 ± 357.07
        MP Cycle 1 (n=121)
    -109.66 ± 338.68
        MP Cycle 2 (n=103)
    -87.79 ± 226.60
        MP Cycle 3 (n=85)
    -53.56 ± 307.61
        MP Cycle 4 (n=68)
    -84.56 ± 196.65
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS, defined as the time from initiation of study treatment to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Baseline to the first occurrence of disease progression or death from any cause (whichever occurs first) (up to approximately 36 months)
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    154
    Units: months
        median (confidence interval 95%)
    6.3 (5.85 to 6.41)
    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, defined as the time from initiation of study treatment to death from any cause.
    End point type
    Secondary
    End point timeframe
    Baseline until death (up to approximately 36 months)
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: months
        median (confidence interval 95%)
    10.0 (8.60 to 11.93)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR, defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions >= 4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1).
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 36 months
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    154
    Units: Percentage of Participants
    number (not applicable)
        ORR during study: Yes
    68.83
        ORR during study: No
    31.17
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Baseline to disease progression or death from any cause (whichever occurs first) up to approximately 36 months
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    106
    Units: months
        median (confidence interval 95%)
    5.2 (4.86 to 5.59)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    DCR, defined as PR, CR and stable disease (SD) as determined by the investigator according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 36 months
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    147
    Units: percentage
    number (not applicable)
        DCR during study: Yes
    93.20
        DCR during study: No
    6.80
    No statistical analyses for this end point

    Secondary: PFS Rate at 6 Months and 1 Year

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    End point title
    		 PFS Rate at 6 Months and 1 Year
    End point description
    PFS rate at 6 months and 1 year, defined as the proportion of patients who have not experienced disease progression or death from any cause at 6 months and 1 year separately, as determined by the investigator according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Baseline up to 1 year
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    154
    Units: percentage
    number (confidence interval 95%)
        PFS at 6 months
    55.84 (47.64 to 63.27)
        PFS at 12 months
    13.36 (8.53 to 19.28)
    No statistical analyses for this end point

    Secondary: OS Rate at 6 months, 12 months, 18 months and 24 months

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    End point title
    		 OS Rate at 6 months, 12 months, 18 months and 24 months
    End point description
    OS rate at 6 months, 12 months, 18 months and 24 months, defined as the proportion of patients who have not experienced death from any cause at 6 months, 12 months, 18 months and 24 months.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 months or death, whichever occurs first
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    154
    Units: percentage of participants
    number (confidence interval 95%)
        OS at 6 months
    76.13 (68.60 to 82.09)
        OS at 12 months
    41.73 (33.90 to 49.37)
        OS at 18 months
    24.53 (18.02 to 31.59)
        OS at 24 months
    17.72 (12.10 to 24.22)
    No statistical analyses for this end point

    Secondary: Time to Treatment Discontinuation (TTD)

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    End point title
    		 Time to Treatment Discontinuation (TTD)
    End point description
    TTD, defined as the time from inclusion to treatment discontinuation for any reason.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 36 months
    End point values
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Number of subjects analysed
    155
    Units: months
        median (confidence interval 95%)
    5.9 (5.12 to 6.45)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline up to 24 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    v25.1
    Reporting groups
    Reporting group title
    Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Reporting group description
    		 Participants will receive the following treatment regimen: atezolizumab + cisplatin/carboplatin + etoposide. Induction treatment will be administered on a 21-day cycle for four or six cycles (according to investigator's choice). Following the induction phase, participants will continue maintenance therapy with atezolizumab. Participants will be treated until loss of clinical benefit, or unaccepted toxicity, or withdrawal of consent, or death (whichever occurs first).

    Serious adverse events
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    76 / 155 (49.03%)
         number of deaths (all causes)
    128
         number of deaths resulting from adverse events
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder Transitional Cell Carcinoma
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Superior Vena Cava Syndrome
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Pyrexia
         subjects affected / exposed
    4 / 155 (2.58%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory Failure
         subjects affected / exposed
    4 / 155 (2.58%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pneumonitis
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory Acidosis
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Neutrophil Count Decreased
         subjects affected / exposed
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    White Blood Cell Count Decreased
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Radiation Oesophagitis
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Atrial Flutter
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Nervous System Disorder
         subjects affected / exposed
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ataxia
         subjects affected / exposed
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Paraneoplastic Myelopathy
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cognitive Disorder
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune-Mediated Encephalitis
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Optic Neuritis
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Myoclonus
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    4 / 155 (2.58%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Thrombocytopenia
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    18 / 155 (11.61%)
         occurrences causally related to treatment / all
    3 / 23
         deaths causally related to treatment / all
    0 / 1
    Myelosuppression
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Visual Impairment
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 155 (1.94%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Disorder
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal Ischaemia
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Intestinal Obstruction
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Nausea
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Small Intestinal Perforation
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Chlolecystitis
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    4 / 155 (2.58%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Nephritis
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Immune-Mediated Myositis
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Back Pain
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 155 (2.58%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Fournier's Gangrene
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    COVID-19 Pneumonia
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Anal Abscess
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 155 (1.94%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    COVID-19
         subjects affected / exposed
    3 / 155 (1.94%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    Pneumonia Staphylococcal
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic Shock
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suspected COVID-19
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Hypoglycaemia
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Atezolizumab + Cisplatin/Carboplatin + Etoposide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    153 / 155 (98.71%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 155 (5.16%)
         occurrences all number
    8
    General disorders and administration site conditions
    Oedema Peripheral
         subjects affected / exposed
    23 / 155 (14.84%)
         occurrences all number
    25
    Asthenia
         subjects affected / exposed
    79 / 155 (50.97%)
         occurrences all number
    111
    Pain
         subjects affected / exposed
    12 / 155 (7.74%)
         occurrences all number
    12
    Gait Disturbance
         subjects affected / exposed
    13 / 155 (8.39%)
         occurrences all number
    14
    Mucosal Inflammation
         subjects affected / exposed
    17 / 155 (10.97%)
         occurrences all number
    18
    Chest Pain
         subjects affected / exposed
    18 / 155 (11.61%)
         occurrences all number
    20
    Fatigue
         subjects affected / exposed
    22 / 155 (14.19%)
         occurrences all number
    26
    Pyrexia
         subjects affected / exposed
    23 / 155 (14.84%)
         occurrences all number
    33
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    34 / 155 (21.94%)
         occurrences all number
    39
    Dyspnoea
         subjects affected / exposed
    34 / 155 (21.94%)
         occurrences all number
    37
    Productive Cough
         subjects affected / exposed
    8 / 155 (5.16%)
         occurrences all number
    9
    Psychiatric disorders
    Depression
         subjects affected / exposed
    8 / 155 (5.16%)
         occurrences all number
    8
    Anxiety
         subjects affected / exposed
    10 / 155 (6.45%)
         occurrences all number
    10
    Insomnia
         subjects affected / exposed
    13 / 155 (8.39%)
         occurrences all number
    13
    Investigations
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    8 / 155 (5.16%)
         occurrences all number
    9
    Blood Creatinine Increased
         subjects affected / exposed
    14 / 155 (9.03%)
         occurrences all number
    22
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    15 / 155 (9.68%)
         occurrences all number
    20
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    17 / 155 (10.97%)
         occurrences all number
    34
    Alanine Aminotransferase Increased
         subjects affected / exposed
    18 / 155 (11.61%)
         occurrences all number
    35
    Platelet Count Decreased
         subjects affected / exposed
    20 / 155 (12.90%)
         occurrences all number
    39
    Neutrophil Count Decreased
         subjects affected / exposed
    29 / 155 (18.71%)
         occurrences all number
    56
    White Blood Cell Count Decreased
         subjects affected / exposed
    8 / 155 (5.16%)
         occurrences all number
    18
    Nervous system disorders
    Headache
         subjects affected / exposed
    24 / 155 (15.48%)
         occurrences all number
    28
    Dizziness
         subjects affected / exposed
    16 / 155 (10.32%)
         occurrences all number
    22
    Dysgeusia
         subjects affected / exposed
    9 / 155 (5.81%)
         occurrences all number
    10
    Paraesthesia
         subjects affected / exposed
    13 / 155 (8.39%)
         occurrences all number
    16
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    24 / 155 (15.48%)
         occurrences all number
    36
    Neutropenia
         subjects affected / exposed
    51 / 155 (32.90%)
         occurrences all number
    77
    Anaemia
         subjects affected / exposed
    72 / 155 (46.45%)
         occurrences all number
    97
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    10 / 155 (6.45%)
         occurrences all number
    12
    Dysphagia
         subjects affected / exposed
    9 / 155 (5.81%)
         occurrences all number
    9
    Dry Mouth
         subjects affected / exposed
    8 / 155 (5.16%)
         occurrences all number
    8
    Abdominal Pain
         subjects affected / exposed
    12 / 155 (7.74%)
         occurrences all number
    14
    Vomiting
         subjects affected / exposed
    27 / 155 (17.42%)
         occurrences all number
    33
    Diarrhoea
         subjects affected / exposed
    32 / 155 (20.65%)
         occurrences all number
    55
    Nausea
         subjects affected / exposed
    41 / 155 (26.45%)
         occurrences all number
    53
    Constipation
         subjects affected / exposed
    47 / 155 (30.32%)
         occurrences all number
    58
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    15 / 155 (9.68%)
         occurrences all number
    15
    Rash
         subjects affected / exposed
    15 / 155 (9.68%)
         occurrences all number
    15
    Alopecia
         subjects affected / exposed
    33 / 155 (21.29%)
         occurrences all number
    34
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    8 / 155 (5.16%)
         occurrences all number
    9
    Endocrine disorders
    Hypothyrodism
         subjects affected / exposed
    15 / 155 (9.68%)
         occurrences all number
    21
    Hyperthyroidism
         subjects affected / exposed
    15 / 155 (9.68%)
         occurrences all number
    16
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    20 / 155 (12.90%)
         occurrences all number
    24
    Myalgia
         subjects affected / exposed
    10 / 155 (6.45%)
         occurrences all number
    10
    Back Pain
         subjects affected / exposed
    20 / 155 (12.90%)
         occurrences all number
    21
    Pain in Extremity
         subjects affected / exposed
    12 / 155 (7.74%)
         occurrences all number
    12
    Infections and infestations
    Respiratory Tract Infection
         subjects affected / exposed
    9 / 155 (5.81%)
         occurrences all number
    10
    Urinary Tract Infection
         subjects affected / exposed
    11 / 155 (7.10%)
         occurrences all number
    12
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    44 / 155 (28.39%)
         occurrences all number
    49
    Hypomagnesaemia
         subjects affected / exposed
    18 / 155 (11.61%)
         occurrences all number
    20
    Hyponatraemia
         subjects affected / exposed
    13 / 155 (8.39%)
         occurrences all number
    14
    Hyperglycaemia
         subjects affected / exposed
    12 / 155 (7.74%)
         occurrences all number
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jul 2020
    - The new Nanostring GeoMx® Digital Space Profiler (DSP) technology will be applied to the tissue samples submitted at baseline - The information about FoundationOneLiquid® was updated to reflect the current test specifications. - Exclusion Criteria section was clarified on patients who are positive for human immunodeficiency virus and who are allowed in the study. - ‘Permitted Therapy’ section added consolidation radiotherapy. - ‘Tumor and Response Evaluation’ section was clarified in case a PET-CT scan with no contrast was performed within permitted Screening window, it could be used as baseline test and was clarified that after completion of induction phase tumor assessment, tumor assessments will be required every 9 weeks thereafter. - In ‘Laboratory Assessments and Biomarker Samples’, for pregnancy test, added local practice is to do it in serum at every cycle. -In ‘Screening and Baseline Assessments’ section, information on validity of tumor assessments has been amended. - In ‘Assessments during Treatment’ section, information on validity of tests was amended. - Option to switch from cisplatin to carboplatin due to inacceptable toxicity was included in chemotherapy management sections. - Text of sections ‘Subgroup Analyses’, ‘Biomarker Analyses’ and Interim Analyses was updated to reflect statistical plan as per current Protocol. - CTCAE version was updated from v.4 to v.5. - The 30-day timeframe to report special situations and non serious AEs associated with special situations is specified.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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