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    Clinical Trial Results:
    A Phase 3 Randomized, Double-Blind, Placebo-controlled Trial of Pembrolizumab (MK-3475/SCH900475) in Combination with Etoposide/Platinum (Cisplatin or Carboplatin) for the First-line Treatment of Subjects with Extensive Stage Small Cell Lung Cancer (KEYNOTE-604)

    Summary
    EudraCT number
    		 2016-004309-15
    Trial protocol
    		 DE   GB   ES   PL   FR   HU  
    Global end of trial date
    21 Sep 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Sep 2022
    First version publication date
    22 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3475-604
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03066778
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck: KEYNOTE-604, JAPIC-CTI: 173744
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.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
    21 Sep 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess the safety and efficacy of pembrolizumab plus standard of care (SOC) chemotherapy (etoposide/platinum [EP]) in participants with newly diagnosed extensive stage small cell lung cancer who have not previously received systemic therapy. The primary study hypotheses are that pembrolizumab+EP prolongs Progression-free Survival per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review and Overall Survival compared with placebo+EP. In this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. With protocol Amendment 07 (03-Oct-2018), the outcome measure of “Change from Baseline at Weeks 12 and 24 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale” was replaced with a single time point analysis at Week 18.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 May 2017
    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
    Australia: 14
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    Chile: 14
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Hungary: 33
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Israel: 29
    Country: Number of subjects enrolled
    Japan: 35
    Country: Number of subjects enrolled
    Korea, Republic of: 35
    Country: Number of subjects enrolled
    Poland: 29
    Country: Number of subjects enrolled
    Russian Federation: 25
    Country: Number of subjects enrolled
    Spain: 39
    Country: Number of subjects enrolled
    Switzerland: 14
    Country: Number of subjects enrolled
    Taiwan: 14
    Country: Number of subjects enrolled
    Turkey: 33
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 57
    Worldwide total number of subjects
    453
    EEA total number of subjects
    142
    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)
    216
    From 65 to 84 years
    237
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants in the pembrolizumab+EP arm were eligible to receive second course treatment with pembrolizumab if they met criteria for retreatment. Per protocol, response, progression, patient reported outcomes, or adverse events during second course did not count towards efficacy or safety outcome measures.

    Pre-assignment
    Screening details
    		 One participant who was randomized to pembrolizumab+EP was inadvertently treated with placebo+EP. For efficacy analyses this participant will be included in the arm they were initially randomized into and for safety analyses the participant will be included by treatment received.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab+EP
    Arm description
    		 During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg pembrolizumab administered by intravenous (IV) infusion on Day 1 of each 21-day cycle prior to chemotherapy

    Investigational medicinal product name
    etoposide
    Investigational medicinal product code
    Other name
    TOPOSAR™
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg/m^2 etoposide administered by IV infusion on Days 1, 2, and 3 of each 21-day cycle

    Investigational medicinal product name
    carboplatin
    Investigational medicinal product code
    Other name
    PARAPLATIN®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    area under the plasma drug concentration-time curve (AUC) 5 carboplatin administered by IV infusion on Day 1 of each 21-day cycle

    Investigational medicinal product name
    cisplatin
    Investigational medicinal product code
    Other name
    PLATINOL®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m^2 cisplatin administered by IV infusion on Day 1 of each 21-day cycle

    Arm title
    		 Placebo+EP
    Arm description
    		 During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).
    Arm type
    		 Placebo

    Investigational medicinal product name
    saline placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    saline placebo administered by IV infusion on Day 1 of each 21-day cycle prior to chemotherapy

    Investigational medicinal product name
    etoposide
    Investigational medicinal product code
    Other name
    TOPOSAR™
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg/m^2 etoposide administered by IV infusion on Days 1, 2, and 3 of each 21-day cycle

    Investigational medicinal product name
    carboplatin
    Investigational medicinal product code
    Other name
    PARAPLATIN®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    area under the plasma drug concentration-time curve (AUC) 5 carboplatin administered by IV infusion on Day 1 of each 21-day cycle

    Investigational medicinal product name
    cisplatin
    Investigational medicinal product code
    Other name
    PLATINOL®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m^2 cisplatin administered by IV infusion on Day 1 of each 21-day cycle

    Number of subjects in period 1
    		Pembrolizumab+EP Placebo+EP
    Started
    228
    225
    Treated
    223
    223
    Received Second Course of Pembrolizumab
    1 [1]
    0 [2]
    Completed
    28
    13
    Not completed
    200
    212
         Consent withdrawn by subject
    5
    7
         Death
    195
    205
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone is for added to account for the participant that received a second course of pembrolizumab after the the initial study course was completed.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone is for added to account for the participant that received a second course of pembrolizumab after the the initial study course was completed.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab+EP
    Reporting group description
    		 During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.

    Reporting group title
    Placebo+EP
    Reporting group description
    		 During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).

    Reporting group values
    		 Pembrolizumab+EP Placebo+EP Total
    Number of subjects
    		 228 225 453
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 115 101 216
        From 65-84 years
    		 113 124 237
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.2 ± 8.4 65.2 ± 8.2 -
    Sex: Female, Male
    Units: Participants
        Female
    		 76 83 159
        Male
    		 152 142 294
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 52 34 86
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 0 1
        White
    		 162 177 339
        More than one race
    		 0 1 1
        Unknown or Not Reported
    		 13 13 26
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 6 13 19
        Not Hispanic or Latino
    		 204 192 396
        Unknown or Not Reported
    		 18 20 38
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    An ECOG Performance Status of 0 (Fully active, able to carry on all pre-disease performance without restriction) or 1 (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature) was required for inclusion in the study and randomization was stratified by ECOG score.
    Units: Subjects
        ECOG = 0
    		 60 56 116
        ECOG = 1
    		 168 169 337
    Lactate Dehydrogenase (LDH) Status at Baseline
    Randomization of participants in the study was stratified by LDH measurement at baseline (≤ or > upper limit of normal).
    Units: Subjects
        LDH = ≤ Upper Limit of Normal
    		 100 95 195
        LDH = > Upper Limit of Normal
    		 127 129 256
        LDH Result Missing
    		 1 1 2
    Platinum Therapy Administered
    Randomization of participants was stratified by type of platinum therapy administered during the study.
    Units: Subjects
        Cisplatin
    		 63 66 129
        Carboplatin
    		 161 156 317
        Not Treated with Platinum Therapy
    		 4 3 7

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab+EP
    Reporting group description
    		 During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.

    Reporting group title
    Placebo+EP
    Reporting group description
    		 During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).

    Primary: Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)

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    End point title
    		 Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. PD, as determined by RECIST 1.1, was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. For this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The analysis population consisted of all randomized participants who were included in the treatment group to which they were randomized. The PFS was calculated using the non-parametric Kaplan-Meier method (KM) for censored data and presented for the first course of study treatment per protocol.
    End point type
    Primary
    End point timeframe
    Up to approximately 30.5 months
    End point values
    		 Pembrolizumab+EP Placebo+EP
    Number of subjects analysed
    228
    225
    Units: Months
        median (confidence interval 95%)
    4.8 (4.3 to 5.4)
    4.3 (4.2 to 4.5)
    Statistical analysis title
    		 Hazard Ratio: Pembrolizumab+EP/Placebo+EP
    Statistical analysis description
    Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by platinum chemotherapy, ECOG, and LDH
    Comparison groups
    Pembrolizumab+EP v Placebo+EP
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00069 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.88
    Notes
    [1] - One-sided p-value based on log-rank test stratified by platinum chemotherapy, ECOG, and LDH

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow up. The analysis population consisted of all randomized participants who were included in the treatment group to which they were randomized. The OS was calculated using the non-parametric Kaplan-Meier method for censored data and presented for the first course of study treatment per protocol.
    End point type
    Primary
    End point timeframe
    Up to approximately 30.5 months
    End point values
    		 Pembrolizumab+EP Placebo+EP
    Number of subjects analysed
    228
    225
    Units: Months
        median (confidence interval 95%)
    10.8 (9.2 to 12.9)
    9.7 (8.6 to 10.7)
    Statistical analysis title
    		 Hazard Ratio: Pembrolizumab+EP/Placebo+EP
    Statistical analysis description
    Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by platinum chemotherapy, ECOG, and LDH
    Comparison groups
    Pembrolizumab+EP v Placebo+EP
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01643 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 0.98
    Notes
    [2] - One-sided p-value based on log-rank test stratified by platinum chemotherapy, ECOG, and LDH

    Secondary: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)

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    End point title
    		 Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
    End point description
    ORR was defined as the percentage of participants who achieve a best objective response of complete response (CR) or partial response (PR) per RECIST 1.1. CR was defined as the disappearance of all target lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions taking as a reference the baseline sum diameters. In this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The analysis population consisted of all randomized participants who were included in the treatment group to which they were randomized. The ORR was calculated using the Miettinen & Nurminen method stratified by type of platinum therapy (carboplatin or cisplatin), baseline ECOG performance status (0 or 1), and baseline LDH (≤ or > upper limit of normal) and presented for the first course of study treatment per protocol.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30.5 months
    End point values
    		 Pembrolizumab+EP Placebo+EP
    Number of subjects analysed
    228
    225
    Units: Percentage of Participants
        number (confidence interval 95%)
    70.6 (64.2 to 76.4)
    61.8 (55.1 to 68.2)
    Statistical analysis title
    		 Percent Difference
    Statistical analysis description
    Based on Miettinen & Nurminen method stratified by platinum chemotherapy, ECOG, and LDH. Cisplatin, ECOG 0, LDH ≤ULN and Cisplatin, ECOG 0, LDH >ULN were combined into one stratum because of small sample size
    Comparison groups
    Pembrolizumab+EP v Placebo+EP
    Number of subjects included in analysis
    453
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0227 [3]
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Percent Difference
    Point estimate
    8.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 17.4
    Notes
    [3] - One-sided p-value for testing. H0: difference in percent = 0 versus H1: difference in percent >0

    Secondary: Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)

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    End point title
    		 Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
    End point description
    DOR was defined as the time from first documented evidence of a CR or PR per RECIST 1.1 until first instance of PD per RECIST 1.1 or death of any cause. CR=disappearance of all target lesions. PR=≥30% decrease in the sum of diameters (SOD) of target lesions taking the baseline SOD as reference. PD=≥20% increase in SOD. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The analysis population=all randomized participants who were included in the treatment group to which they were randomized and experienced a CR or PR. The DOR was calculated using the KM method for censored data and is presented for the first course of study treatment per protocol. 9999=median DOR and upper and lower limits not reached due to no progressive disease by time of last disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30.5 months
    End point values
    		 Pembrolizumab+EP Placebo+EP
    Number of subjects analysed
    161
    139
    Units: Months
        median (full range (min-max))
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Number of Participants Who Experienced an Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could be any unfavourable and unintended sign (i.e. abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the Sponsor’s product, was also an adverse event. The analysis population consisted of all participants who received ≥1 dose of study treatment. The number of participants who experienced an AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30.5 months
    End point values
    		 Pembrolizumab+EP Placebo+EP
    Number of subjects analysed
    223
    223
    Units: Participants
    223
    222
    No statistical analyses for this end point

    Secondary: Number of Participants Discontinuing Study Treatment Due to an Adverse Event (AE)

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    End point title
    		 Number of Participants Discontinuing Study Treatment Due to an Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could be any unfavourable and unintended sign (i.e. abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the Sponsor’s product, was also an adverse event. The analysis population consisted of all participants who received ≥1 dose of study treatment. The number of participants who discontinued due to an AE was reported for each arm according to treatment received and is presented for the first course of study treatment per protocol.
    End point type
    Secondary
    End point timeframe
    Up to approximately 26 months
    End point values
    		 Pembrolizumab+EP Placebo+EP
    Number of subjects analysed
    223
    223
    Units: Participants
    33
    14
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Any Grade 3 to 5 Adverse Events (AE) as Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE 4.03)

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    End point title
    		 Number of Participants Experiencing Any Grade 3 to 5 Adverse Events (AE) as Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE 4.03)
    End point description
    The CTCAE uses Grades 1 through 5 correlating to AE severity criteria. Grade 1=mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2=moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3=severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4=life-threatening consequences; urgent intervention indicated. Grade 5=death related to AE. The analysis population consisted of all participants who received ≥1 dose of study treatment. The number of participants who experienced any Grade 3 to 5 AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30.5 months
    End point values
    		 Pembrolizumab+EP Placebo+EP
    Number of subjects analysed
    223
    223
    Units: Participants
    175
    172
    No statistical analyses for this end point

    Secondary: Change from Baseline at Week 18 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale

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    End point title
    		 Change from Baseline at Week 18 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale
    End point description
    EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all-4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor-7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0-100 using a standard algorithm. Change from baseline scores were calculated using a constrained longitudinal data analysis model. Negative change from baseline values indicated deterioration in health status or functioning; positive change indicated improvement. The analysis population=all participants who received ≥1 dose of study medication and had non-missing assessments at baseline and Week 18. Data are presented for the first course of study treatment per protocol.
    End point type
    Secondary
    End point timeframe
    Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 18
    End point values
    		 Pembrolizumab+EP Placebo+EP
    Number of subjects analysed
    221
    218
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    8.66 (5.26 to 12.06)
    4.23 (0.93 to 7.52)
    Statistical analysis title
    		 Difference in Least Square Means
    Comparison groups
    Pembrolizumab+EP v Placebo+EP
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.04
    Method
    		 Logrank
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    4.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 8.66

    Secondary: Change from Baseline at Week 12 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale

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    End point title
    		 Change from Baseline at Week 12 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale
    End point description
    EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all-4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor-7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0-100 using a standard algorithm. Negative change from baseline values indicated deterioration in health status or functioning; positive change indicated improvement. The analysis population included all participants who received ≥1 dose of treatment and had non-missing assessments at baseline and Week 12. Per protocol data were to be presented for the first course of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 12
    End point values
    		 Pembrolizumab+EP Placebo+EP
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [4] - This outcome measure was replaced with a single time-point analysis at Week 18 with Amendment 7.
    [5] - This outcome measure was replaced with a single time-point analysis at Week 18 with Amendment 7.
    No statistical analyses for this end point

    Secondary: Change from Baseline at Week 24 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale

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    End point title
    		 Change from Baseline at Week 24 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale
    End point description
    EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all-4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor-7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0-100 using a standard algorithm. Negative change from baseline values indicated deterioration in health status or functioning; positive change indicated improvement. The analysis population included all participants who received ≥1 dose of treatment and had non-missing assessments at baseline and Week 24. Per protocol, data were to be presented for the first course of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 24
    End point values
    		 Pembrolizumab+EP Placebo+EP
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [6] - This outcome measure was replaced with a single time-point analysis at Week 18 with Amendment 7.
    [7] - This outcome measure was replaced with a single time-point analysis at Week 18 with Amendment 7.
    No statistical analyses for this end point

    Secondary: Time to True Deterioration (TTD) in the Composite Endpoint of Cough, Chest Pain, and Dyspnea Using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and Lung Cancer Module 13 (QLQ-LC13)

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    End point title
    		 Time to True Deterioration (TTD) in the Composite Endpoint of Cough, Chest Pain, and Dyspnea Using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and Lung Cancer Module 13 (QLQ-LC13)
    End point description
    TTD in patient-reported lung cancer symptoms of cough (QLQ-LC-13 Item 1), chest pain (QLQ-LC-13 Item 10), and dyspnea (QLQ-C30 Item 8) was a composite endpoint defined as: time to first onset of ≥10 point deterioration from baseline in an item confirmed by a second adjacent ≥10 point deterioration. The QLQ-LC13 consists of 13 measures of lung cancer symptoms and side effects from chemotherapy/radiation scored on a 4-point scale (1=none, 2=a little, 3=quite a bit, 4=very much). Scores were transformed to a range of 0-100 using a standard algorithm. Higher scores represented increasing symptom severity. The analysis population=all participants who received ≥1 dose of study medication and had non-missing assessments. TTD was calculated using the product-limit KM method for censored data and is presented for the first course of study treatment per protocol. 9999=Median TTD, lower or upper limit not reached (no protocol-specified deterioration criteria reached by time of last assessment).
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycles 1-9, Day 1 of every other cycle for Cycles 10-17 and 30 days after last dose of study treatment (Up to approximately 27 months)]
    End point values
    		 Pembrolizumab+EP Placebo+EP
    Number of subjects analysed
    221
    218
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    8.7 (5.9 to 9999)
    Statistical analysis title
    		 Hazard Ratio: Pembrolizumab+EP/Placebo+EP
    Statistical analysis description
    Based on Cox regression model with treatment as a covariate stratified by platinum chemotherapy ECOG, and LDH. Cisplatin, ECOG 0, LDH ≤ULN and Cisplatin, ECOG 0, LDH >ULN were combined into one stratum because of small sample size
    Comparison groups
    Pembrolizumab+EP v Placebo+EP
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.208 [8]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.14
    Notes
    [8] - Two-sided p-value based on stratified log-rank test

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First Course: Up to 49.5 months; Second Course: Up to 37.9 months. First and second course dosing occurred concurrently
    Adverse event reporting additional description
    All-cause mortality (ACM)=all randomized participants; AE=participants treated ≥1 dose. Per protocol, MedDRA terms neoplasm progression (NP), malignant NP, disease progression unrelated to treatment are excluded. ACM was adjusted for participant randomized to pembrolizumab+EP and treated with placebo+EP. AEs presented by actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Pembrolizumab+EP
    Reporting group description
    		 During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment.

    Reporting group title
    Pembrolizumab Second Course
    Reporting group description
    		 Participants who met the criteria for retreatment received pembrolizumab 200 mg by IV infusion on Day 1 of each 21-day cycle for up to 1 year of treatment.

    Reporting group title
    Placebo+EP
    Reporting group description
    		 During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).

    Serious adverse events
    		 Pembrolizumab+EP Pembrolizumab Second Course Placebo+EP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    111 / 223 (49.78%)
    1 / 1 (100.00%)
    89 / 223 (39.91%)
         number of deaths (all causes)
    196
    1
    212
         number of deaths resulting from adverse events
    6
    0
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraneoplastic syndrome
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 223 (1.35%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 223 (1.79%)
    0 / 1 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    3 / 3
    Fatigue
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 223 (1.79%)
    0 / 1 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 223 (1.35%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal haemorrhage
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    5 / 223 (2.24%)
    0 / 1 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Pneumothorax
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 223 (2.24%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    4 / 223 (1.79%)
    0 / 1 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limbic encephalitis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parkinsonism
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 1 (100.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 223 (3.14%)
    0 / 1 (0.00%)
    10 / 223 (4.48%)
         occurrences causally related to treatment / all
    6 / 7
    0 / 0
    8 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    15 / 223 (6.73%)
    0 / 1 (0.00%)
    14 / 223 (6.28%)
         occurrences causally related to treatment / all
    15 / 15
    0 / 0
    13 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    11 / 223 (4.93%)
    0 / 1 (0.00%)
    6 / 223 (2.69%)
         occurrences causally related to treatment / all
    10 / 11
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 223 (1.35%)
    0 / 1 (0.00%)
    5 / 223 (2.24%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Autoimmune uveitis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 223 (1.35%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subacute cutaneous lupus erythematosus
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 223 (2.24%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurogenic bladder
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    3 / 223 (1.35%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
    Paracancerous pneumonia
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    17 / 223 (7.62%)
    0 / 1 (0.00%)
    12 / 223 (5.38%)
         occurrences causally related to treatment / all
    3 / 20
    0 / 0
    3 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Serratia sepsis
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 223 (1.35%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 223 (0.00%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    4 / 223 (1.79%)
    0 / 1 (0.00%)
    5 / 223 (2.24%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 1 (0.00%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembrolizumab+EP Pembrolizumab Second Course Placebo+EP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    221 / 223 (99.10%)
    1 / 1 (100.00%)
    216 / 223 (96.86%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 223 (5.38%)
    0 / 1 (0.00%)
    10 / 223 (4.48%)
         occurrences all number
    15
    0
    14
    Hypotension
         subjects affected / exposed
    9 / 223 (4.04%)
    0 / 1 (0.00%)
    16 / 223 (7.17%)
         occurrences all number
    11
    0
    21
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    38 / 223 (17.04%)
    0 / 1 (0.00%)
    43 / 223 (19.28%)
         occurrences all number
    46
    0
    48
    Fatigue
         subjects affected / exposed
    61 / 223 (27.35%)
    0 / 1 (0.00%)
    60 / 223 (26.91%)
         occurrences all number
    76
    0
    78
    Chest pain
         subjects affected / exposed
    11 / 223 (4.93%)
    0 / 1 (0.00%)
    21 / 223 (9.42%)
         occurrences all number
    11
    0
    24
    Oedema peripheral
         subjects affected / exposed
    17 / 223 (7.62%)
    0 / 1 (0.00%)
    26 / 223 (11.66%)
         occurrences all number
    20
    0
    32
    Pyrexia
         subjects affected / exposed
    32 / 223 (14.35%)
    0 / 1 (0.00%)
    14 / 223 (6.28%)
         occurrences all number
    37
    0
    17
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    45 / 223 (20.18%)
    0 / 1 (0.00%)
    45 / 223 (20.18%)
         occurrences all number
    62
    0
    51
    Dyspnoea
         subjects affected / exposed
    37 / 223 (16.59%)
    0 / 1 (0.00%)
    37 / 223 (16.59%)
         occurrences all number
    41
    0
    41
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    25 / 223 (11.21%)
    0 / 1 (0.00%)
    28 / 223 (12.56%)
         occurrences all number
    26
    0
    34
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    17 / 223 (7.62%)
    0 / 1 (0.00%)
    21 / 223 (9.42%)
         occurrences all number
    20
    0
    24
    Aspartate aminotransferase increased
         subjects affected / exposed
    19 / 223 (8.52%)
    0 / 1 (0.00%)
    13 / 223 (5.83%)
         occurrences all number
    22
    0
    15
    Blood creatinine increased
         subjects affected / exposed
    15 / 223 (6.73%)
    0 / 1 (0.00%)
    8 / 223 (3.59%)
         occurrences all number
    23
    0
    8
    Blood alkaline phosphatase increased
         subjects affected / exposed
    12 / 223 (5.38%)
    0 / 1 (0.00%)
    6 / 223 (2.69%)
         occurrences all number
    15
    0
    8
    Weight decreased
         subjects affected / exposed
    22 / 223 (9.87%)
    0 / 1 (0.00%)
    20 / 223 (8.97%)
         occurrences all number
    24
    0
    23
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    31 / 223 (13.90%)
    0 / 1 (0.00%)
    15 / 223 (6.73%)
         occurrences all number
    36
    0
    17
    Headache
         subjects affected / exposed
    29 / 223 (13.00%)
    0 / 1 (0.00%)
    34 / 223 (15.25%)
         occurrences all number
    34
    0
    41
    Dysgeusia
         subjects affected / exposed
    14 / 223 (6.28%)
    0 / 1 (0.00%)
    12 / 223 (5.38%)
         occurrences all number
    14
    0
    13
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    101 / 223 (45.29%)
    0 / 1 (0.00%)
    96 / 223 (43.05%)
         occurrences all number
    122
    0
    115
    Leukopenia
         subjects affected / exposed
    49 / 223 (21.97%)
    0 / 1 (0.00%)
    45 / 223 (20.18%)
         occurrences all number
    84
    0
    70
    Neutropenia
         subjects affected / exposed
    120 / 223 (53.81%)
    0 / 1 (0.00%)
    114 / 223 (51.12%)
         occurrences all number
    217
    0
    207
    Thrombocytopenia
         subjects affected / exposed
    57 / 223 (25.56%)
    0 / 1 (0.00%)
    46 / 223 (20.63%)
         occurrences all number
    85
    0
    80
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    15 / 223 (6.73%)
    0 / 1 (0.00%)
    13 / 223 (5.83%)
         occurrences all number
    18
    0
    13
    Constipation
         subjects affected / exposed
    65 / 223 (29.15%)
    0 / 1 (0.00%)
    59 / 223 (26.46%)
         occurrences all number
    78
    0
    69
    Abdominal pain upper
         subjects affected / exposed
    13 / 223 (5.83%)
    0 / 1 (0.00%)
    5 / 223 (2.24%)
         occurrences all number
    14
    0
    5
    Dyspepsia
         subjects affected / exposed
    12 / 223 (5.38%)
    0 / 1 (0.00%)
    7 / 223 (3.14%)
         occurrences all number
    13
    0
    7
    Dysphagia
         subjects affected / exposed
    12 / 223 (5.38%)
    0 / 1 (0.00%)
    6 / 223 (2.69%)
         occurrences all number
    12
    0
    6
    Diarrhoea
         subjects affected / exposed
    46 / 223 (20.63%)
    0 / 1 (0.00%)
    41 / 223 (18.39%)
         occurrences all number
    67
    0
    48
    Nausea
         subjects affected / exposed
    85 / 223 (38.12%)
    0 / 1 (0.00%)
    96 / 223 (43.05%)
         occurrences all number
    135
    0
    144
    Stomatitis
         subjects affected / exposed
    14 / 223 (6.28%)
    0 / 1 (0.00%)
    15 / 223 (6.73%)
         occurrences all number
    17
    0
    17
    Vomiting
         subjects affected / exposed
    36 / 223 (16.14%)
    0 / 1 (0.00%)
    39 / 223 (17.49%)
         occurrences all number
    48
    0
    49
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    75 / 223 (33.63%)
    0 / 1 (0.00%)
    84 / 223 (37.67%)
         occurrences all number
    77
    0
    87
    Dry skin
         subjects affected / exposed
    13 / 223 (5.83%)
    0 / 1 (0.00%)
    10 / 223 (4.48%)
         occurrences all number
    13
    0
    10
    Erythema
         subjects affected / exposed
    13 / 223 (5.83%)
    0 / 1 (0.00%)
    4 / 223 (1.79%)
         occurrences all number
    14
    0
    4
    Pruritus
         subjects affected / exposed
    25 / 223 (11.21%)
    0 / 1 (0.00%)
    18 / 223 (8.07%)
         occurrences all number
    33
    0
    23
    Rash
         subjects affected / exposed
    30 / 223 (13.45%)
    0 / 1 (0.00%)
    13 / 223 (5.83%)
         occurrences all number
    39
    0
    17
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    12 / 223 (5.38%)
    0 / 1 (0.00%)
    6 / 223 (2.69%)
         occurrences all number
    12
    0
    7
    Hypothyroidism
         subjects affected / exposed
    26 / 223 (11.66%)
    0 / 1 (0.00%)
    5 / 223 (2.24%)
         occurrences all number
    27
    0
    5
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 1 (100.00%)
    1 / 223 (0.45%)
         occurrences all number
    1
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    29 / 223 (13.00%)
    0 / 1 (0.00%)
    19 / 223 (8.52%)
         occurrences all number
    37
    0
    22
    Back pain
         subjects affected / exposed
    25 / 223 (11.21%)
    0 / 1 (0.00%)
    26 / 223 (11.66%)
         occurrences all number
    27
    0
    27
    Pain in extremity
         subjects affected / exposed
    12 / 223 (5.38%)
    0 / 1 (0.00%)
    13 / 223 (5.83%)
         occurrences all number
    15
    0
    16
    Musculoskeletal chest pain
         subjects affected / exposed
    12 / 223 (5.38%)
    0 / 1 (0.00%)
    6 / 223 (2.69%)
         occurrences all number
    14
    0
    6
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    12 / 223 (5.38%)
    0 / 1 (0.00%)
    13 / 223 (5.83%)
         occurrences all number
    13
    0
    14
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 223 (7.62%)
    0 / 1 (0.00%)
    13 / 223 (5.83%)
         occurrences all number
    22
    0
    16
    Nasopharyngitis
         subjects affected / exposed
    12 / 223 (5.38%)
    0 / 1 (0.00%)
    9 / 223 (4.04%)
         occurrences all number
    15
    0
    9
    Urinary tract infection
         subjects affected / exposed
    10 / 223 (4.48%)
    1 / 1 (100.00%)
    8 / 223 (3.59%)
         occurrences all number
    12
    1
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    69 / 223 (30.94%)
    0 / 1 (0.00%)
    54 / 223 (24.22%)
         occurrences all number
    85
    0
    68
    Hypokalaemia
         subjects affected / exposed
    15 / 223 (6.73%)
    0 / 1 (0.00%)
    13 / 223 (5.83%)
         occurrences all number
    20
    0
    19
    Hyponatraemia
         subjects affected / exposed
    21 / 223 (9.42%)
    0 / 1 (0.00%)
    16 / 223 (7.17%)
         occurrences all number
    26
    0
    23

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2017
    Amendment 1 corrected a typographical error in the numbering of the inclusion criteria.
    14 Mar 2017
    Amendment 2 corrected the timeframe associated with the exclusion criterion for major surgery.
    17 Apr 2017
    Amendment 3 removed the option to crossover from the placebo+ etoposide+platinum arm to pembrolizumab treatment after documentation of progressive disease.
    06 Jul 2017
    Amendment 4 removed the requirement for unblinding treatment assignment after documentation of progressive disease because the option to cross over to pembrolizumab was removed and, with it, the need to unblind.
    11 Sep 2017
    Amendment 5 clarified the exclusion criterion regarding study participation for participants with brain metastases.
    21 Dec 2017
    Amendment 6 updated the dose modification guidelines for pembrolizumab to include information regarding the treatment of myocarditis, revised the requirements for survival follow-up to allow for more frequent data collection, and added a Day 8 visit during Cycles 1 through 4 to allow for more frequent safety monitoring.
    06 Nov 2018
    Amendment 7 updated criteria for the first and second interim analyses to calendar time from the time the first patient was randomized to ensure sufficient follow-up time for PFS analyses and manage the gap between the first two interim analysis, changed the alpha spending strategy for PFS to calendar time to align with the interim analyses, and changed the alpha allocation between the primary (OS and PFS) and key secondary (ORR) hypothesis on the basis of accumulating external data on PFS and OS in immunotherapy-chemotherapy combinations in small cell lung cancer to allow more alpha to be allocated to the primary endpoints.
    15 Jan 2019
    Amendment 8 changed the alpha spending function for PFS analysis from Hwang Shih DeCani to Lan-DeMets O’Brien Fleming, the alpha spending approach was changed from time-based to information fraction-based spending, the assumption for median PFS in the control arm was changed to 4.3 months based on external data published from other clinical trials, and the power and efficacy bound calculations were updated to reflect the change in PFS median assumption and an alpha spending approach.
    24 May 2019
    Amendment 9 updated criteria for the final OS analysis to be a minimum of 294 events, or 31 months from study start, whichever occurs later to ensure sufficient follow-up time for the final OS analysis, added clarification to describe the alpha-spending strategy for PFS and OS in detail, and corrected a publishing error in Amendment 08.

    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
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