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    Clinical Trial Results:
    A Phase III Randomized Trial of MK-3475 (Pembrolizumab) versus Standard Treatment in Subjects with Recurrent or Metastatic Head and Neck Cancer

    Summary
    EudraCT number
    		 2014-001749-26
    Trial protocol
    		 IE   LT   DE   BE   PT   NL   HU   IT   ES   FR   PL   SE  
    Global end of trial date

    Results information
    Results version number
    		 v2
    This version publication date
    18 Oct 2018
    First version publication date
    18 May 2018
    Other versions
    		 v1 , v3
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-3475-040
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02252042
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., 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
    Interim
    Date of interim/final analysis
    15 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2017
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This is a study of pembrolizumab (MK-3475) versus standard treatment (methotrexate, docetaxel or cetuximab) for the treatment of recurrent or metastatic head and neck squamous cell cancer (HNSCC). Participants will be randomly assigned to receive either pembrolizumab or Investigator's choice of standard treatment. The primary study hypothesis is that pembrolizumab treatment prolongs Overall Survival (OS) when compared to standard treatment.
    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
    17 Nov 2014
    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: 5
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    France: 51
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Korea, Republic of: 22
    Country: Number of subjects enrolled
    Lithuania: 7
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Portugal: 30
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Switzerland: 18
    Country: Number of subjects enrolled
    United Kingdom: 54
    Country: Number of subjects enrolled
    United States: 94
    Worldwide total number of subjects
    495
    EEA total number of subjects
    287
    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)
    332
    From 65 to 84 years
    162
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This results disclosure is based on a data cutoff date of 15 May 2017, at which time 99 participants were ongoing in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab
    Arm description
    		 Participants received pembrolizumab 200 mg intravenous (IV) on Day 1 of each 3-week cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475
    Other name
    KEYTRUDA®
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg via intravenous (IV) infusion

    Arm title
    		 Active Comparator
    Arm description
    		 Participants received methotrexate 40 mg/m^2 IV (may have been escalated to 60 mg/m^2 maximum dose) on Days 1, 8, and 15 of each 3-week cycle; or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle; or cetuximab 400 mg/m^2 IV loading dose on Day 1 and 250 mg/m^2 IV on Days 8 and 15 of Cycle 1, followed by cetuximab 250 mg/m^2 on Days 1, 8, and 15 of each subsequent 3-week cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    OTREXUP™ RASUVO® RHEUMATREX® TREXALL™
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg/m^2 IV infusion (may be escalated to 60 mg/m^2 maximum dose)

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    ERBITUX®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Loading dose: 400 mg/m^2 via IV infusion Maintenance dose: 250 mg/m^2 via IV infusion

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    TAXOTERE®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m^2 via IV infusion

    Number of subjects in period 1
    		Pembrolizumab Active Comparator
    Started
    247
    248
    Treated
    246
    234
    Completed
    0
    0
    Not completed
    247
    248
         Adverse event, serious fatal
    170
    192
         Consent withdrawn by subject
    13
    20
         Physician decision
    -
    1
         Ongoing in study
    64
    35

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenous (IV) on Day 1 of each 3-week cycle.

    Reporting group title
    Active Comparator
    Reporting group description
    		 Participants received methotrexate 40 mg/m^2 IV (may have been escalated to 60 mg/m^2 maximum dose) on Days 1, 8, and 15 of each 3-week cycle; or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle; or cetuximab 400 mg/m^2 IV loading dose on Day 1 and 250 mg/m^2 IV on Days 8 and 15 of Cycle 1, followed by cetuximab 250 mg/m^2 on Days 1, 8, and 15 of each subsequent 3-week cycle.

    Reporting group values
    		 Pembrolizumab Active Comparator Total
    Number of subjects
    		 247 248 495
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 165 167 332
        From 65-84 years
    		 81 81 162
        85 years and over
    		 1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.3 ( 9.8 ) 60.2 ( 8.6 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 40 43 83
        Male
    		 207 205 412
    Programmed Cell Death-Ligand 1 (PD-L1) Expression Level: Tumor Proportion Score (TPS)
    Participants were assessed for their PD-L1 tumor expression level by immunohistochemistry assay using tumor tissue from a newly obtained biopsy. Participants with a TPS ≥50% were classified as PD-L1 strongly positive and participants with a TPS <50% were classified as not strongly positive.
    Units: Subjects
        TPS=0%
    		 103 93 196
        1%<=TPS<50%
    		 79 87 166
        TPS >=50%
    		 64 65 129
        Missing
    		 1 3 4
    Race (NIH/OMB)
    The race of participants is presented.
    Units: Subjects
        American Indian or Alaska Native
    		 2 0 2
        Asian
    		 15 16 31
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 3 7 10
        White
    		 207 207 414
        More than one race
    		 4 3 7
        Unknown or Not Reported
    		 16 15 31
    Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
    Participants were assessed for ECOG PS: Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory & able to carry out work of a light or sedentary nature; Grade 2: Ambulatory & capable of all selfcare but unable to carry out any work activities, up & about more than 50% of waking hours; Grade 3: Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; Grade 4: Completely disabled, cannot carry on any selfcare, totally confined to bed or chair or Grade 5: Dead.
    Units: Subjects
        EGOG PS=0
    		 71 67 138
        ECOG PS=1
    		 176 180 356
        ECOG PS=2
    		 0 1 1
    Human Papillomavirus (HPV) Tumor Status
    Participants were assessed for the presence or absence of HPV in their tumors.
    Units: Subjects
        Positive HPV Status
    		 61 58 119
        Negative HPV Status
    		 186 190 376
    PD-L1 Combined Positive Score (CPS) Status
    Participants were assessed for their PD-L1 tumor expression level by immunohistochemistry assay using tumor tissue from a newly obtained biopsy. Participants with a CPS ≥1 were classified as PD-L1 positive and participants with a CPS <1 were classified as PD-L1 negative.
    Units: Subjects
        PD-L1 CPS <1
    		 50 54 104
        PD-L1 CPS ≥1
    		 196 191 387
        Missing
    		 1 3 4

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenous (IV) on Day 1 of each 3-week cycle.

    Reporting group title
    Active Comparator
    Reporting group description
    		 Participants received methotrexate 40 mg/m^2 IV (may have been escalated to 60 mg/m^2 maximum dose) on Days 1, 8, and 15 of each 3-week cycle; or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle; or cetuximab 400 mg/m^2 IV loading dose on Day 1 and 250 mg/m^2 IV on Days 8 and 15 of Cycle 1, followed by cetuximab 250 mg/m^2 on Days 1, 8, and 15 of each subsequent 3-week cycle.

    Subject analysis set title
    Pembrolizumab with PD-L1≥1% CPS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All randomized participants who received Pembrolizumab and had PD-L1 ≥1% CPS. Participants are included in the treatment arm to which they were randomized.

    Subject analysis set title
    Active Comparator with PD-L1≥1% CPS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All randomized participants with PD-L1 ≥1% CPS who received Active Comparator. Participants are included in the treatment group to which they were randomized.

    Subject analysis set title
    Pembrolizumab with CR or PR
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All randomized participants who received Pembrolizumab and demonstrated a Complete Response (CR) or Partial Response (PR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Participants are included in the treatment arm to which they were randomized.

    Subject analysis set title
    Active Comparator with CR or PR
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All randomized participants who received Active Comparator and demonstrated a CR or PR according to RECIST 1.1. Participants are included in the treatment arm to which they were randomized.

    Subject analysis set title
    Pembrolizumab with PD-L1≥1% CPS and CR or PR
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All randomized participants who received Pembrolizumab, had PD-L1≥1% CPS and experienced a CR or PR. Participants are included in the treatment arm to which they were randomized.

    Subject analysis set title
    Active Comparator with PD-L1≥1% CPS and CR or PR
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All randomized participants who received Active Comparator, had PD-L1≥1% CPS and experienced a CR or PR. Participants are included in the treatment arm to which they were randomized.

    Primary: Initial Overall Survival (OS) for All Participants

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    End point title
    		 Initial Overall Survival (OS) for All Participants
    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 final analysis were to be censored at the date of the last follow-up. The OS for all participants is presented. These initial OS results are based on a data cutoff date of 15-May-2017 with a database lock date of 04-Jun-2017. At the time of the database lock of 04-Jun-2017, there was incomplete collection of survival data for 12 participants. The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Up to approximately 2 years (Database lock on 04-Jun-2017)
    End point values
    		 Pembrolizumab Active Comparator
    Number of subjects analysed
    247
    248
    Units: Months
        median (confidence interval 95%)
    8.5 (6.4 to 9.5)
    7.1 (5.9 to 8.1)
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly Positive)
    Comparison groups
    Pembrolizumab v Active Comparator
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0316
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.01

    Primary: Updated Final OS for All Participants

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    End point title
    		 Updated Final OS for All Participants
    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 final analysis were to be censored at the date of the last follow-up. The updated OS for all participants is presented. These OS results are after complete acquisition of all outstanding survival data using a 15-May-2017 data cutoff date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Up to approximately 2 years (Database update on 13-Oct-2017)
    End point values
    		 Pembrolizumab Active Comparator
    Number of subjects analysed
    247
    248
    Units: Months
        median (confidence interval 95%)
    8.4 (6.4 to 9.4)
    6.9 (5.9 to 8.0)
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly Positive). Pembrolizumab is the numerator; Active Comparator is the denominator.
    Comparison groups
    Pembrolizumab v Active Comparator
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01605
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 0.98

    Secondary: OS for Participants With PD-L1-Positive Expression Defined by ≥1% CPS (PD-L1 ≥1% CPS)

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    End point title
    		 OS for Participants With PD-L1-Positive Expression Defined by ≥1% CPS (PD-L1 ≥1% CPS)
    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 final analysis will be censored at the date of the last follow-up. The OS for all participants with PD-L1 expression ≥1% CPS is presented. These efficacy results are after complete acquisition of all outstanding survival data using a 15-May-2017 data cutoff date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab with PD-L1≥1% CPS Active Comparator with PD-L1≥1% CPS
    Number of subjects analysed
    196
    191
    Units: Months
        median (confidence interval 95%)
    8.7 (6.9 to 11.4)
    7.1 (5.7 to 8.3)
    Statistical analysis title
    		 OS Hazard Ratio, CPS≥1% CPS
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly Positive). Pembrolizumab is the numerator; Active Comparator is the denominator.
    Comparison groups
    Pembrolizumab with PD-L1≥1% CPS v Active Comparator with PD-L1≥1% CPS
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00493
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 0.93

    Secondary: Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for All Participants

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    End point title
    		 Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for All Participants
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 for all participants is presented. These efficacy results are after complete acquisition of all outstanding survival data using a 15-May-2017 data cutoff date with a database update date of 13-Oct-2017.The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Active Comparator
    Number of subjects analysed
    247
    248
    Units: Months
        median (confidence interval 95%)
    2.1 (2.1 to 2.3)
    2.3 (2.1 to 2.8)
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly Positive). Pembrolizumab is the numerator; Active Comparator is the denominator.
    Comparison groups
    Pembrolizumab v Active Comparator
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32504
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.16

    Secondary: PFS per RECIST 1.1 in Participants With PD-L1 ≥1% CPS

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    End point title
    		 PFS per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
    End point description
    PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 for all participants with PD-L1 expression ≥1% CPS is presented. These efficacy results are after complete acquisition of all outstanding survival data using a 15-May-2017 data cutoff date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab with PD-L1≥1% CPS Active Comparator with PD-L1≥1% CPS
    Number of subjects analysed
    196
    191
    Units: Months
        median (confidence interval 95%)
    2.2 (2.1 to 3.0)
    2.3 (2.1 to 3.0)
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Cox regression model with treatment as a single covariate. Pembrolizumab is the numerator; Active Comparator is the denominator.
    Comparison groups
    Pembrolizumab with PD-L1≥1% CPS v Active Comparator with PD-L1≥1% CPS
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07736
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.06

    Secondary: Objective Response Rate (ORR) per RECIST 1.1 in All Participants

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    End point title
    		 Objective Response Rate (ORR) per RECIST 1.1 in All Participants
    End point description
    ORR was defined as the percentage of the participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based on blinded central imaging vendor review with or without confirmation. The ORR per RECIST 1.1 for all participants is presented. These efficacy results are after complete acquisition of all outstanding survival data using a 15-May-2017 data cutoff date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Active Comparator
    Number of subjects analysed
    247
    248
    Units: Percentage of Participants
        number (confidence interval 95%)
    14.6 (10.4 to 19.6)
    10.1 (6.6 to 14.5)
    Statistical analysis title
    		 Difference in Percentages
    Statistical analysis description
    Stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly Positive). H0: difference in %=0; H1: difference in %>0.
    Comparison groups
    Pembrolizumab v Active Comparator
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.061
    Method
    		 Logrank
    Parameter type
    		 Difference in percentages
    Point estimate
    4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 10.6

    Secondary: ORR per RECIST 1.1 in Participants With PD-L1 ≥1% CPS

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    End point title
    		 ORR per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
    End point description
    ORR was defined as the percentage of the participants in the analysis population who had a CR (Disappearance of all target lesions) or a PR (At least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1 based on blinded central imaging vendor review with or without confirmation. The ORR per RECIST 1.1 for all participants with PD-L1 expression ≥1% CPS is presented. These efficacy results are after complete acquisition of all outstanding survival data using a 15-May-2017 data cutoff date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab with PD-L1≥1% CPS Active Comparator with PD-L1≥1% CPS
    Number of subjects analysed
    196
    191
    Units: Percentage of Participants
        number (confidence interval 95%)
    17.3 (12.3 to 23.4)
    9.9 (6.1 to 15.1)
    Statistical analysis title
    		 Difference in Percentages
    Statistical analysis description
    Stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly Positive). H0: difference in %=0; H1: difference in %>0
    Comparison groups
    Pembrolizumab with PD-L1≥1% CPS v Active Comparator with PD-L1≥1% CPS
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0171
    Method
    		 Logrank
    Parameter type
    		 Difference in percentages
    Point estimate
    7.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 14.6

    Secondary: Duration of Response (DOR) per RECIST 1.1 in All Participants

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    End point title
    		 Duration of Response (DOR) per RECIST 1.1 in All Participants
    End point description
    For participants who demonstrated a confirmed CR or PR per RECIST 1.1, DOR was defined as the time from first documented evidence of confirmed CR or PR per RECIST 1.1 until PD per RECIST 1.1 or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. DOR assessments were based on blinded central imaging vendor review with confirmation. The DOR per RECIST 1.1 for all participants who experienced a confirmed CR or PR is presented. These efficacy results are after complete acquisition of all outstanding survival data using a 15-May-2017 data cutoff date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants who demonstrated a confirmed CR or PR per RECIST 1.1. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab with CR or PR Active Comparator with CR or PR
    Number of subjects analysed
    26
    18
    Units: Months
        median (full range (min-max))
    18.4 (2.7 to 18.4)
    5.0 (1.4 to 18.8)
    No statistical analyses for this end point

    Secondary: DOR per RECIST 1.1 in Participants With PD-L1 ≥1% CPS

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    End point title
    		 DOR per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
    End point description
    For participants who demonstrated a confirmed CR or PR per RECIST 1.1, DOR was defined as the time from 1st documented evidence of CR or PR per RECIST 1.1 until PD per RECIST 1.1 or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition, the sum must also have demonstrated an absolute increase of ≥5 mm. DOR assessments were based on blinded central imaging vendor review with confirmation. The DOR per RECIST 1.1 for all participants with PD-L1 ≥1% CPS who experienced a confirmed CR or PR is presented. These efficacy results are after complete acquisition of all outstanding survival data using a 15-May-2017 data cutoff date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS who demonstrated a confirmed CR or PR per RECIST 1.1. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab with PD-L1≥1% CPS and CR or PR Active Comparator with PD-L1≥1% CPS and CR or PR
    Number of subjects analysed
    26
    15
    Units: Months
        median (full range (min-max))
    18.4 (2.7 to 18.4)
    9.6 (1.4 to 18.8)
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP) per RECIST 1.1 in All Participants

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    End point title
    		 Time to Progression (TTP) per RECIST 1.1 in All Participants
    End point description
    TTP was defined as the time from randomization to the first documented PD based on assessments by the blinded central imaging vendor review per RECIST 1.1. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. The TTP per RECIST 1.1 for all participants is presented. These efficacy results are after complete acquisition of all outstanding survival data using a 15-May-2017 data cutoff date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Active Comparator
    Number of subjects analysed
    247
    248
    Units: Months
        median (confidence interval 95%)
    2.2 (2.1 to 3.3)
    2.2 (2.1 to 3.4)
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly Positive)
    Comparison groups
    Pembrolizumab v Active Comparator
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.14545 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.12
    Notes
    [1] - p-value stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly Positive)

    Secondary: TTP per RECIST 1.1 in Participants With PD-L1 ≥1% CPS

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    End point title
    		 TTP per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
    End point description
    TTP was defined as the time from randomization to the first documented PD based on assessments by the blinded central imaging vendor review per RECIST 1.1. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. The TTP per RECIST 1.1 for all participants with PD-L1 ≥1% CPS is presented. These efficacy results are after complete acquisition of all outstanding survival data using a 15-May-2017 data cutoff date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab with PD-L1≥1% CPS Active Comparator with PD-L1≥1% CPS
    Number of subjects analysed
    196
    191
    Units: Months
        median (full range (min-max))
    2.7 (2.1 to 3.5)
    2.3 (2.1 to 3.4)
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly. Positive)
    Comparison groups
    Pembrolizumab with PD-L1≥1% CPS v Active Comparator with PD-L1≥1% CPS
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05851 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.06
    Notes
    [2] - p-value stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly Positive)

    Secondary: PFS per Modified RECIST in All Participants

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    End point title
    		 PFS per Modified RECIST in All Participants
    End point description
    PFS was defined as the time from randomization to the 1st documented PD on per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition, the sum must also have demonstrated an absolute increase of ≥5 mm. Modified RECIST is similar to RECIST 1.1 with the exception that confirmation assessment of PD (≥4 weeks after the initial PD assessment) was required for participants who remained on treatment following documented PD per RECIST 1.1. The PFS per modified RECIST for all participants is presented. These efficacy results are after complete acquisition of all outstanding survival data using a 15-May-2017 data cutoff date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Active Comparator
    Number of subjects analysed
    247
    248
    Units: Months
        median (confidence interval 95%)
    3.5 (3.1 to 4.4)
    4.8 (4.1 to 5.7)
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly Positive). Pembrolizumab is the numerator; Active Comparator is the denominator.
    Comparison groups
    Pembrolizumab v Active Comparator
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65759
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.27

    Secondary: PFS per Modified RECIST 1.1 in Participants With PD-L1 ≥1% CPS

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    End point title
    		 PFS per Modified RECIST 1.1 in Participants With PD-L1 ≥1% CPS
    End point description
    PFS was defined as the time from randomization to the 1st documented PD per RECIST 1.1 based on blinded central imaging vendor review or death, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition, the sum must also have demonstrated an absolute increase of ≥5 mm. Modified RECIST is similar to RECIST 1.1 with the exception that a confirmation assessment of PD (≥4 weeks after the initial PD assessment) was required for participants who remained on treatment following a documented PD per RECIST 1.1. The PFS per modified RECIST for all participants with PD-L1 ≥1% CPS is presented. These efficacy results are after complete acquisition of all outstanding survival data using a 15-May-2017 data cutoff date with a database update date of 13-Oct-2017. The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab with PD-L1≥1% CPS Active Comparator with PD-L1≥1% CPS
    Number of subjects analysed
    196
    191
    Units: Months
        median (confidence interval 95%)
    3.6 (3.1 to 4.6)
    4.8 (4.1 to 5.7)
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Cox regression model with treatment as a covariate stratified by ECOG PS (0 vs. 1), HPV status (Positive vs. Negative) & PD-L1 status (Strongly Positive, Not Strongly. Pembrolizumab is the numerator; Active Comparator is the denominator. Positive).
    Comparison groups
    Pembrolizumab with PD-L1≥1% CPS v Active Comparator with PD-L1≥1% CPS
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51982
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.26

    Secondary: Number of Participants Who Experienced At Least One Adverse Event (AE) in All Participants

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    End point title
    		 Number of Participants Who Experienced At Least One Adverse Event (AE) in All Participants
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The number of all participants who experienced at least one AE is presented. The safety population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months
    End point values
    		 Pembrolizumab Active Comparator
    Number of subjects analysed
    246
    234
    Units: Participants
    238
    227
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced At Least One AE in Participants With PD-L1 ≥1% CPS

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    End point title
    		 Number of Participants Who Experienced At Least One AE in Participants With PD-L1 ≥1% CPS
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The number of all participants with PD-L1 ≥1% CPS who experienced at least one AE is presented. The safety population consisted of all randomized participants with PD-L1 ≥1% CPS who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months
    End point values
    		 Pembrolizumab with PD-L1≥1% CPS Active Comparator with PD-L1≥1% CPS
    Number of subjects analysed
    195
    183
    Units: Participants
    192
    178
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Treatment Due to an AE in All Participants

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    End point title
    		 Number of Participants Who Discontinued Study Treatment Due to an AE in All Participants
    End point description
    The number of all participants who discontinued study treatment due to an AE is presented. The safety population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab Active Comparator
    Number of subjects analysed
    246
    234
    Units: Participants
    28
    37
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Treatment Due to an AE in Participants With PD-L1 ≥1% CPS

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    End point title
    		 Number of Participants Who Discontinued Study Treatment Due to an AE in Participants With PD-L1 ≥1% CPS
    End point description
    The number of all participants with PD-L1 ≥1% CPS who discontinued study treatment due to an AE is presented. The safety population consisted of all randomized participants with PD-L1 ≥1% CPS who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    End point values
    		 Pembrolizumab with PD-L1≥1% CPS Active Comparator with PD-L1≥1% CPS
    Number of subjects analysed
    195
    183
    Units: Participants
    24
    30
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 27 months (Up to 90 days after last dose of study drug)
    Adverse event reporting additional description
    Participants with ≥1 dose of study drug. Per protocol, progression of study cancer was not a serious AE (SAE) unless related to study drug. MedDRA terms "Neoplasm progression", "Malignant neoplasm progression" & "Disease progression" unrelated to study drug are excluded as SAEs. Drug-related deaths are reported as “Malignant Neoplasm Progression”.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Active Comparator
    Reporting group description
    		 Participants received methotrexate 40 mg/m^2 IV (may have been escalated to 60 mg/m^2 maximum dose) on Days 1, 8, and 15 of each 3-week cycle; or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle; or cetuximab 400 mg/m^2 IV loading dose on Day 1 and 250 mg/m^2 IV on Days 8 and 15 of Cycle 1, followed by cetuximab 250 mg/m^2 on Days 1, 8, and 15 of each subsequent 3-week cycle.

    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle.

    Serious adverse events
    		 Active Comparator Pembrolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    92 / 234 (39.32%)
    110 / 246 (44.72%)
         number of deaths (all causes)
    207
    181
         number of deaths resulting from adverse events
    2
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Astrocytoma, low grade
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Paraneoplastic syndrome
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    2 / 234 (0.85%)
    9 / 246 (3.66%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 10
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Tumour pain
         subjects affected / exposed
    2 / 234 (0.85%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Angiodysplasia
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 234 (1.71%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 4
    1 / 5
    Euthanasia
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Face oedema
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ill-defined disorder
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 234 (0.85%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 234 (1.28%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asphyxia
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 234 (0.43%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Eosinophilic pneumonia
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal obstruction
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal fistula
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    3 / 234 (1.28%)
    6 / 246 (2.44%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 234 (1.28%)
    6 / 246 (2.44%)
         occurrences causally related to treatment / all
    0 / 3
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 234 (0.85%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Respiratory tract haemorrhage
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    3 / 234 (1.28%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    2 / 234 (0.85%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fall
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Femoral neck fracture
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative fever
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site ulcer
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheostomy malfunction
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paresis
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 234 (0.85%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    9 / 234 (3.85%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    8 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph node haemorrhage
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 234 (0.43%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 234 (0.85%)
    6 / 246 (2.44%)
         occurrences causally related to treatment / all
    2 / 2
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    3 / 234 (1.28%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 234 (0.85%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Malignant dysphagia
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    3 / 234 (1.28%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral discharge
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    3 / 234 (1.28%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cirrhosis alcoholic
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungating wound
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    2 / 234 (0.85%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Kyphosis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue haemorrhage
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 234 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 234 (0.85%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated tuberculosis
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected fistula
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 234 (0.85%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral bacterial infection
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    2 / 234 (0.85%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    16 / 234 (6.84%)
    20 / 246 (8.13%)
         occurrences causally related to treatment / all
    4 / 17
    1 / 21
         deaths causally related to treatment / all
    1 / 5
    0 / 6
    Pulmonary sepsis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 234 (1.28%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stoma site infection
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 234 (0.85%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 234 (0.00%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 234 (1.28%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 234 (0.00%)
    7 / 246 (2.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 234 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Active Comparator Pembrolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    210 / 234 (89.74%)
    212 / 246 (86.18%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    7 / 234 (2.99%)
    13 / 246 (5.28%)
         occurrences all number
    8
    13
    Vascular disorders
    Hypotension
         subjects affected / exposed
    12 / 234 (5.13%)
    12 / 246 (4.88%)
         occurrences all number
    16
    12
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    41 / 234 (17.52%)
    37 / 246 (15.04%)
         occurrences all number
    52
    47
    Fatigue
         subjects affected / exposed
    63 / 234 (26.92%)
    48 / 246 (19.51%)
         occurrences all number
    81
    51
    Mucosal inflammation
         subjects affected / exposed
    36 / 234 (15.38%)
    17 / 246 (6.91%)
         occurrences all number
    51
    21
    Pyrexia
         subjects affected / exposed
    25 / 234 (10.68%)
    24 / 246 (9.76%)
         occurrences all number
    35
    38
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    36 / 234 (15.38%)
    42 / 246 (17.07%)
         occurrences all number
    39
    47
    Dyspnoea
         subjects affected / exposed
    26 / 234 (11.11%)
    30 / 246 (12.20%)
         occurrences all number
    31
    32
    Haemoptysis
         subjects affected / exposed
    6 / 234 (2.56%)
    13 / 246 (5.28%)
         occurrences all number
    8
    15
    Productive cough
         subjects affected / exposed
    5 / 234 (2.14%)
    14 / 246 (5.69%)
         occurrences all number
    7
    14
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 234 (2.56%)
    13 / 246 (5.28%)
         occurrences all number
    6
    13
    Insomnia
         subjects affected / exposed
    17 / 234 (7.26%)
    22 / 246 (8.94%)
         occurrences all number
    17
    22
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    13 / 234 (5.56%)
    10 / 246 (4.07%)
         occurrences all number
    18
    10
    Neutrophil count decreased
         subjects affected / exposed
    24 / 234 (10.26%)
    4 / 246 (1.63%)
         occurrences all number
    29
    11
    Platelet count decreased
         subjects affected / exposed
    13 / 234 (5.56%)
    7 / 246 (2.85%)
         occurrences all number
    19
    7
    Weight decreased
         subjects affected / exposed
    26 / 234 (11.11%)
    21 / 246 (8.54%)
         occurrences all number
    26
    22
    White blood cell count decreased
         subjects affected / exposed
    12 / 234 (5.13%)
    2 / 246 (0.81%)
         occurrences all number
    15
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    22 / 234 (9.40%)
    21 / 246 (8.54%)
         occurrences all number
    24
    25
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    51 / 234 (21.79%)
    62 / 246 (25.20%)
         occurrences all number
    70
    77
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    12 / 234 (5.13%)
    9 / 246 (3.66%)
         occurrences all number
    12
    9
    Constipation
         subjects affected / exposed
    37 / 234 (15.81%)
    43 / 246 (17.48%)
         occurrences all number
    43
    49
    Diarrhoea
         subjects affected / exposed
    41 / 234 (17.52%)
    36 / 246 (14.63%)
         occurrences all number
    50
    54
    Dry mouth
         subjects affected / exposed
    6 / 234 (2.56%)
    15 / 246 (6.10%)
         occurrences all number
    6
    15
    Dysphagia
         subjects affected / exposed
    15 / 234 (6.41%)
    21 / 246 (8.54%)
         occurrences all number
    16
    23
    Nausea
         subjects affected / exposed
    44 / 234 (18.80%)
    34 / 246 (13.82%)
         occurrences all number
    52
    43
    Stomatitis
         subjects affected / exposed
    26 / 234 (11.11%)
    7 / 246 (2.85%)
         occurrences all number
    34
    9
    Vomiting
         subjects affected / exposed
    23 / 234 (9.83%)
    23 / 246 (9.35%)
         occurrences all number
    34
    27
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    27 / 234 (11.54%)
    1 / 246 (0.41%)
         occurrences all number
    27
    1
    Dermatitis acneiform
         subjects affected / exposed
    18 / 234 (7.69%)
    0 / 246 (0.00%)
         occurrences all number
    28
    0
    Dry skin
         subjects affected / exposed
    17 / 234 (7.26%)
    4 / 246 (1.63%)
         occurrences all number
    19
    4
    Pruritus
         subjects affected / exposed
    17 / 234 (7.26%)
    18 / 246 (7.32%)
         occurrences all number
    40
    22
    Rash
         subjects affected / exposed
    38 / 234 (16.24%)
    25 / 246 (10.16%)
         occurrences all number
    81
    32
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    9 / 234 (3.85%)
    37 / 246 (15.04%)
         occurrences all number
    9
    40
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 234 (2.14%)
    19 / 246 (7.72%)
         occurrences all number
    6
    20
    Back pain
         subjects affected / exposed
    8 / 234 (3.42%)
    23 / 246 (9.35%)
         occurrences all number
    8
    24
    Neck pain
         subjects affected / exposed
    17 / 234 (7.26%)
    19 / 246 (7.72%)
         occurrences all number
    17
    19
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    43 / 234 (18.38%)
    31 / 246 (12.60%)
         occurrences all number
    48
    37
    Hypercalcaemia
         subjects affected / exposed
    13 / 234 (5.56%)
    14 / 246 (5.69%)
         occurrences all number
    14
    16
    Hypokalaemia
         subjects affected / exposed
    19 / 234 (8.12%)
    23 / 246 (9.35%)
         occurrences all number
    21
    27
    Hypomagnesaemia
         subjects affected / exposed
    20 / 234 (8.55%)
    10 / 246 (4.07%)
         occurrences all number
    25
    11
    Hyponatraemia
         subjects affected / exposed
    16 / 234 (6.84%)
    12 / 246 (4.88%)
         occurrences all number
    17
    14
    Hypophosphataemia
         subjects affected / exposed
    12 / 234 (5.13%)
    15 / 246 (6.10%)
         occurrences all number
    14
    21

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2015
    Amendment 01: Increased sample size from 466 to 600 participants, added hypotheses, and added statistical analyses for the PD-L1 Strong Positive (TPS >50% PD-L1) population; Inclusion/Exclusion criteria modifications were made to align with program standards.
    16 Apr 2016
    Amendment 10: Decreased the sample size from 600 to 466 subjects, downgraded OS in the PD-L1 positive subjects and PFS from primary hypotheses to key secondary hypotheses, replaced hypotheses on the PD-L1 population with hypotheses on the CPS ≥1 population, promoted ORR to the key secondary endpoints, updated language to include PD-L1 status masking, and included the role of unblended Sponsor personnel.
    02 Nov 2016
    Amendment 11: Updated, in the Statistical Analysis Plan, the alpha-spending language, power calculation, and timing of the final analysis to reflect the change to the number of death events at the final analysis.
    20 Feb 2018
    Amendment 12: Added text and updated Dose Modification Guidelines for Pembrolizumab and added text to enable survival follow-up activities throughout the study.

    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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