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    Clinical Trial Results:
    A Randomized, Double-Blind, Phase 3 Study of Pemetrexed + Platinum Chemotherapy with or without Pembrolizumab (MK-3475) in TKI-resistant EGFR-mutated Tumors in Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) Participants (KEYNOTE-789)

    Summary
    EudraCT number
    		 2017-004188-11
    Trial protocol
    		 SE   ES   FR   DE   GB   IT  
    Global end of trial date
    02 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Oct 2024
    First version publication date
    10 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3475-789
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03515837
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@msd.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp and Dohme LLC, ClinicalTrialsDisclosure@msd.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Oct 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the efficacy and safety of pemetrexed plus platinum chemotherapy (carboplatin or cisplatin) with or without pembrolizumab (MK-3475; KEYTRUDA®) in the treatment of adults with the following types of tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutated, metastatic non-squamous non-small cell lung cancer (NSCLC) tumors: 1) TKI-failures (including osimertinib [TAGRISSO®] failure) with T790M-negative mutation tumors, 2) T790M-positive mutation tumors with prior exposure to osimertinib, and 3) first-line osimertinib failure regardless of T790M mutation status. The primary study hypotheses are that the combination of pembrolizumab plus chemotherapy has superior efficacy compared to saline placebo plus chemotherapy in terms of Progression-free Survival (PFS) and Overall Survival (OS). Upon study completion, participants are discontinued and may be enrolled in a pembrolizumab extension study, if available.
    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
    29 Jun 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    China: 112
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Hong Kong: 13
    Country: Number of subjects enrolled
    Israel: 17
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    Japan: 79
    Country: Number of subjects enrolled
    Korea, Republic of: 52
    Country: Number of subjects enrolled
    Mexico: 23
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    Taiwan: 44
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    492
    EEA total number of subjects
    90
    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)
    272
    From 65 to 84 years
    218
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Of 855 participants screened, 492 randomized; of these, 491 received treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembro + Pemetrexed + Chemo
    Arm description
    		 Participants received pembrolizumab (pembro) 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo) (either carboplatin Area Under the Curve [AUC] 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m^2 via IV infusion Q3W for 4 cycles (Cycles 1-4).

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Area Under the Curve (AUC) 5 via IV infusion Q3W for 4 cycles (Cycles 1-4)

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475, SCH-900475, KEYTRUDA®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles

    Arm title
    		 Placebo + Pemetrexed + Chemo
    Arm description
    		 Participants received normal saline solution via IV infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo)(either carboplatin AUC 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]). Eligible participants who had BICR-verified progressive disease were eligible to switch over to pembrolizumab monotherapy 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline placebo to pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Saline placebo administered via IV infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475, SCH-900475, KEYTRUDA®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    After meeting protocol requirements for ending placebo treatment, pembrolizumab could have been administered 200 mg via IV infusion Q3W for up to 35 cycles

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m^2 via IV infusion Q3W for 4 cycles (Cycles 1-4).

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Area Under the Curve (AUC) 5 via IV infusion Q3W for 4 cycles (Cycles 1-4)

    Number of subjects in period 1
    		Pembro + Pemetrexed + Chemo Placebo + Pemetrexed + Chemo
    Started
    245
    247
    Treated
    245
    246
    Switched over to Pembro monotherapy
    0
    50
    Completed
    0
    0
    Not completed
    245
    247
         Adverse event, serious fatal
    219
    227
         Consent withdrawn by subject
    -
    4
         Participation Was Terminated By Sponsor
    26
    15
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembro + Pemetrexed + Chemo
    Reporting group description
    		 Participants received pembrolizumab (pembro) 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo) (either carboplatin Area Under the Curve [AUC] 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]).

    Reporting group title
    Placebo + Pemetrexed + Chemo
    Reporting group description
    		 Participants received normal saline solution via IV infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo)(either carboplatin AUC 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]). Eligible participants who had BICR-verified progressive disease were eligible to switch over to pembrolizumab monotherapy 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles.

    Reporting group values
    		 Pembro + Pemetrexed + Chemo Placebo + Pemetrexed + Chemo Total
    Number of subjects
    		 245 247 492
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 146 126 272
        From 65-84 years
    		 97 121 218
        85 years and over
    		 2 0 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 61.7 ( 10.9 ) 63.1 ( 10.0 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 152 151 303
        Male
    		 93 96 189
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 3 3 6
        Asian
    		 165 163 328
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 2 5 7
        White
    		 67 72 139
        More than one race
    		 1 0 1
        Unknown or Not Reported
    		 7 4 11
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 16 19 35
        Not Hispanic or Latino
    		 222 221 443
        Unknown or Not Reported
    		 7 7 14
    Previous use of Tyrosine Kinase Inhibitor (TKI) Treatment History with Osimertinib
    Participants were stratified using previous treatment history with TKI osimertinib: osimertinib or no osimertinib.
    Units: Subjects
        Treated with TKI except for Osimertinib
    		 128 126 254
        Treated with first line Osimertinib
    		 28 33 61
        Treated with second line Osimertinib
    		 88 88 176
        Other
    		 1 0 1
    Geographic Region: East Asia
    Participants were stratified by geographic area of the enrolling site: East Asia versus Non-East Asia
    Units: Subjects
        East Asia
    		 150 150 300
        Non-East Asia
    		 95 97 192
    Geographic Region: US
    Participants were stratified by geographic area of the enrolling site: United States versus Non-United States
    Units: Subjects
        US
    		 3 6 9
        Non-EU
    		 242 241 483
    Geographic Region: EU
    Participants were stratified by geographic area of the enrolling site: European Union versus Non-European Union
    Units: Subjects
        EU
    		 53 47 100
        Non-EU
    		 192 200 392
    Programmed Death Ligand 1 (PD-L1) Status
    Participants were assessed for their PD-L1 tumor expression level by immunohistochemistry assay using tumor tissue from a newly obtained biopsy. PD-L1 status is determined by tumor proportion score (TPS). 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 ≥ 50%
    		 52 51 103
        TPS <50%
    		 181 185 366
        Not evaluable
    		 12 11 23
    Programmed Death Ligand 1 Status
    Participants were assessed for their PD-L1 tumor expression level by immunohistochemistry assay using tumor tissue from a newly obtained biopsy. PD-L1 status is determined by tumor proportion score (TPS). 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 ≥ 50%
    		 52 51 103
        TPS ≥1% AND ≤49%
    		 54 72 126
        TPS <1%
    		 127 113 240
        Not evaluable
    		 12 11 23

    End points

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    End points reporting groups
    Reporting group title
    Pembro + Pemetrexed + Chemo
    Reporting group description
    		 Participants received pembrolizumab (pembro) 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo) (either carboplatin Area Under the Curve [AUC] 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]).

    Reporting group title
    Placebo + Pemetrexed + Chemo
    Reporting group description
    		 Participants received normal saline solution via IV infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo)(either carboplatin AUC 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]). Eligible participants who had BICR-verified progressive disease were eligible to switch over to pembrolizumab monotherapy 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles.

    Primary: Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. PFS was assessed by blinded independent central review (BICR) using RECIST 1.1. Per RECIST 1.1, PD is 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 demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions is also considered PD. The PFS presented was analyzed using the product-limit (Kaplan-Meier) method for censored data. The analysis population included all randomized participants who received at least 1 dose of study intervention.
    End point type
    Primary
    End point timeframe
    Up to ~40 months
    End point values
    		 Pembro + Pemetrexed + Chemo Placebo + Pemetrexed + Chemo
    Number of subjects analysed
    245
    247
    Units: Months
        median (confidence interval 95%)
    5.6 (5.5 to 5.8)
    5.5 (5.4 to 5.6)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Hazard ratio with "Pembro + Pemetrexed + Chemo" as numerator and "Placebo + Pemetrexed + Chemo" as denominator. Hazard ratio based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by PD-L1 expression; treatment history; geographic region of the enrolling site.
    Comparison groups
    Pembro + Pemetrexed + Chemo v Placebo + Pemetrexed + Chemo
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0122 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 0.97
    Notes
    [1] - One-sided p-value based on log-rank test stratified by PD-L1 expression; treatment history; geographic region of the enrolling site.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is 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 presented was analyzed using the product-limit (Kaplan-Meier) method for censored data. The analysis population included all randomized participants who received at least 1 dose of study intervention.
    End point type
    Primary
    End point timeframe
    Up to ~51 months
    End point values
    		 Pembro + Pemetrexed + Chemo Placebo + Pemetrexed + Chemo
    Number of subjects analysed
    245
    247
    Units: Months
        median (confidence interval 95%)
    15.9 (13.7 to 18.8)
    14.7 (12.7 to 17.1)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Hazard ratio with "Pembro + Pemetrexed + Chemo" as numerator and "Placebo + Pemetrexed + Chemo" as denominator. Hazard ratio based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by PD-L1 expression; treatment history; geographic region of the enrolling site.
    Comparison groups
    Pembro + Pemetrexed + Chemo v Placebo + Pemetrexed + Chemo
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0362 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.02
    Notes
    [2] - One-sided p-value based on log-rank test stratified by PD-L1 expression; treatment history; geographic region of the enrolling site.

    Secondary: Objective Response Rate (ORR) Per RECIST 1.1

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    End point title
    		 Objective Response Rate (ORR) Per RECIST 1.1
    End point description
    ORR was assessed by BICR using RECIST 1.1. ORR is defined as the percentage of participants in the analysis population who experience 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, taking as reference the baseline sum diameters) per RECIST 1.1. The ORR for participants is presented. The analysis population included all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    Up to ~51 months
    End point values
    		 Pembro + Pemetrexed + Chemo Placebo + Pemetrexed + Chemo
    Number of subjects analysed
    245
    247
    Units: Percentage of Participants
        number (confidence interval 95%)
    29.0 (23.4 to 35.1)
    27.1 (21.7 to 33.1)
    Statistical analysis title
    		 Mean Difference (Final Values)
    Statistical analysis description
    Mean difference in final values: "Pembro + Pemetrexed + Chemo" minus "Placebo + Pemetrexed + Chemo". Based on Miettinen & Nurminen method stratified by PD-L1 expression; treatment history; geographic region of the enrolling site.
    Comparison groups
    Pembro + Pemetrexed + Chemo v Placebo + Pemetrexed + Chemo
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 9.9

    Secondary: Duration of Response (DOR) Per RECIST 1.1

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    End point title
    		 Duration of Response (DOR) Per RECIST 1.1
    End point description
    DOR was assessed by BICR using RECIST 1.1. For participants who experience a response of CR or PR, DOR is defined as the time from the earliest date of qualifying response until earliest date of PD or death from any cause, whichever comes first. The DOR presented was analyzed using the product-limit (Kaplan-Meier) method for censored data. The analysis population included all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    Up to ~51 months
    End point values
    		 Pembro + Pemetrexed + Chemo Placebo + Pemetrexed + Chemo
    Number of subjects analysed
    245
    246
    Units: Months
        median (confidence interval 95%)
    6.3 (5.9 to 8.3)
    5.6 (4.4 to 6.3)
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score

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    End point title
    		 Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score
    End point description
    The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions regarding Global Health Status (GHS; "How would you rate your overall health during the past week?") and Quality of Life (QoL; "How would you rate your overall quality of life during the past week?") are each scored on a 7-point scale (1=Very poor to 7=Excellent). The two raw scores were averaged into a combined score, then normalized using linear transformation so each participant’s score ranged from 0 to 100 (0=Worst overall health/quality of life and 100=Best overall health/quality of life). The change from baseline in GHS (EORTC QLQ-C30 Item 29) and QoL (EORTC QLQ-C30 Item 30) combined score is presented. The analysis population included all randomized participants who had at least 1 patient reported outcome (PRO) assessment available and had received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 18
    End point values
    		 Pembro + Pemetrexed + Chemo Placebo + Pemetrexed + Chemo
    Number of subjects analysed
    241
    243
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    -0.46 (-3.17 to 2.25)
    -2.05 (-4.74 to 0.64)
    Statistical analysis title
    		 Difference in Least Squares (LS) Means
    Statistical analysis description
    Difference in LS Means: "Pembro + Pemetrexed + Chemo" minus "Placebo + Pemetrexed + Chemo". Based on a cLDA model with the PRO scores as the response variable with covariates for treatment by time interaction, stratification factors PD-L1 expression, treatment history, and geographic region of the enrolling site as covariates.
    Comparison groups
    Pembro + Pemetrexed + Chemo v Placebo + Pemetrexed + Chemo
    Number of subjects included in analysis
    484
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.93
         upper limit
    		 5.1

    Secondary: Time to True Deterioration (TTD) in the EORTC Questionnaire Composite Endpoint of Cough, Chest Pain or Dyspnea

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    End point title
    		 Time to True Deterioration (TTD) in the EORTC Questionnaire Composite Endpoint of Cough, Chest Pain or Dyspnea
    End point description
    TTD is the time from baseline to first onset of 10 points or more deterioration from baseline with confirmation by the subsequent visit of 10 points or more deterioration from baseline in the composite endpoint of cough [EORTC QLQ-Lung Cancer Module 13 (LC13) Item 1; How much did you cough?], chest pain [EORTC QLQ-LC13 Item 10; Have you had pain in your chest?], or dyspnea [EORTC QLQ-C30 Item 8; Were you short of breath?]. Individual responses are given on a 4-point scale (1=Not at all; 4=Very much), with a lower score indicating a better outcome. TTD was analyzed using the product-limit (Kaplan-Meier) method for censored data. The time to true deterioration in the composite endpoint of cough, chest pain or dyspnea is presented. The analysis population included all randomized participants who had at least 1 patient reported outcome (PRO) assessment available and had received at least 1 dose of study intervention. 9999 = Median and/or upper range time to deterioration were not reached.
    End point type
    Secondary
    End point timeframe
    Baseline and up to ~51 months
    End point values
    		 Pembro + Pemetrexed + Chemo Placebo + Pemetrexed + Chemo
    Number of subjects analysed
    237
    236
    Units: Months
        median (confidence interval 95%)
    9999 (10.05 to 9999)
    17.97 (6.67 to 9999)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Hazard ratio with "Pembro + Pemetrexed + Chemo" as numerator and "Placebo + Pemetrexed + Chemo" as denominator. Hazard ratio based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by PD-L1 expression; treatment history; geographic region of the enrolling site.
    Comparison groups
    Pembro + Pemetrexed + Chemo v Placebo + Pemetrexed + Chemo
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.27

    Secondary: Percentage of participants who experienced an adverse event (AE)

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    End point title
    		 Percentage of participants who experienced an adverse event (AE)
    End point description
    An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The percentage of participants who experienced an AE is presented. The analysis population included all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    Up to ~44 months
    End point values
    		 Pembro + Pemetrexed + Chemo Placebo + Pemetrexed + Chemo
    Number of subjects analysed
    245
    246
    Units: Percentage of Participants
        number (not applicable)
    97.6
    98.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Discontinued Study Treatment Due to AEs

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    End point title
    		 Percentage of Participants who Discontinued Study Treatment Due to AEs
    End point description
    An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The percentage of participants who discontinued study treatment due to an adverse event is presented. The analysis population included all randomized participants who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    Up to ~41 months
    End point values
    		 Pembro + Pemetrexed + Chemo Placebo + Pemetrexed + Chemo
    Number of subjects analysed
    245
    246
    Units: Percentage of Participants
        number (not applicable)
    19.2
    17.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to ~59 months
    Adverse event reporting additional description
    AEs include all participants who received ≥1 dose of study drug. Deaths include all randomized participants. Per protocol, progression of cancer under study was not an AE unless related to study treatment. Thus, MedDRA terms "Neoplasm progression", "Malignant neoplasm progression" & "Disease progression" not related to treatment are excluded as AEs
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Pembro + Pemetrexed + Chemo
    Reporting group description
    		 Participants received pembrolizumab (pembro) 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo) (either carboplatin Area Under the Curve [AUC] 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]).

    Reporting group title
    Placebo +Pemetrexed +Chemo Switched Over to Pembro monotherapy
    Reporting group description
    		 Participants who received placebo + pemetrexed + chemo per their randomized treatment assignment and had BICR-verified progressive disease were eligible to receive pembrolizumab monotherapy 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles.

    Reporting group title
    Placebo + Pemetrexed + Chemo
    Reporting group description
    		 Participants received normal saline solution via IV infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo)(either carboplatin AUC 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]). Eligible participants who had BICR-verified progressive disease were eligible to switch over to pembrolizumab monotherapy 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles.

    Serious adverse events
    		 Pembro + Pemetrexed + Chemo Placebo +Pemetrexed +Chemo Switched Over to Pembro monotherapy Placebo + Pemetrexed + Chemo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    86 / 245 (35.10%)
    8 / 50 (16.00%)
    70 / 246 (28.46%)
         number of deaths (all causes)
    219
    44
    186
         number of deaths resulting from adverse events
    5
    0
    12
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Small cell lung cancer
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 245 (0.41%)
    1 / 50 (2.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Sudden death
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    5 / 245 (2.04%)
    1 / 50 (2.00%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Fatigue
         subjects affected / exposed
    2 / 245 (0.82%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatomegaly
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    7 / 245 (2.86%)
    0 / 50 (0.00%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated lung disease
         subjects affected / exposed
    0 / 245 (0.00%)
    1 / 50 (2.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 245 (0.82%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 245 (1.63%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 245 (1.63%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    5 / 245 (2.04%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    8 / 245 (3.27%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    9 / 9
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    5 / 245 (2.04%)
    0 / 50 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count increased
         subjects affected / exposed
    0 / 245 (0.00%)
    1 / 50 (2.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Spinal fracture
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 245 (0.82%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    5 / 245 (2.04%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stroke in evolution
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vocal cord paresis
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 245 (2.45%)
    0 / 50 (0.00%)
    8 / 246 (3.25%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Febrile neutropenia
         subjects affected / exposed
    4 / 245 (1.63%)
    0 / 50 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniere's disease
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular hole
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 245 (0.82%)
    0 / 50 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mesenteric artery thrombosis
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 245 (0.82%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal ulcer haemorrhage
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 245 (0.82%)
    0 / 50 (0.00%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis acute
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Lichenoid keratosis
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 245 (0.00%)
    1 / 50 (2.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated nephritis
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 245 (0.41%)
    1 / 50 (2.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    2 / 245 (0.82%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 245 (0.82%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 245 (0.00%)
    0 / 50 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 245 (3.27%)
    1 / 50 (2.00%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    Endocarditis
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 245 (0.82%)
    0 / 50 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 245 (0.00%)
    1 / 50 (2.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fulminant type 1 diabetes mellitus
         subjects affected / exposed
    1 / 245 (0.41%)
    0 / 50 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    4 / 245 (1.63%)
    0 / 50 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembro + Pemetrexed + Chemo Placebo +Pemetrexed +Chemo Switched Over to Pembro monotherapy Placebo + Pemetrexed + Chemo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    233 / 245 (95.10%)
    31 / 50 (62.00%)
    225 / 246 (91.46%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 245 (4.49%)
    0 / 50 (0.00%)
    14 / 246 (5.69%)
         occurrences all number
    16
    0
    15
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    29 / 245 (11.84%)
    0 / 50 (0.00%)
    28 / 246 (11.38%)
         occurrences all number
    41
    0
    31
    Chest pain
         subjects affected / exposed
    17 / 245 (6.94%)
    3 / 50 (6.00%)
    9 / 246 (3.66%)
         occurrences all number
    17
    3
    10
    Fatigue
         subjects affected / exposed
    60 / 245 (24.49%)
    1 / 50 (2.00%)
    49 / 246 (19.92%)
         occurrences all number
    81
    1
    81
    Malaise
         subjects affected / exposed
    18 / 245 (7.35%)
    1 / 50 (2.00%)
    23 / 246 (9.35%)
         occurrences all number
    31
    1
    30
    Oedema peripheral
         subjects affected / exposed
    28 / 245 (11.43%)
    1 / 50 (2.00%)
    24 / 246 (9.76%)
         occurrences all number
    42
    2
    28
    Pyrexia
         subjects affected / exposed
    33 / 245 (13.47%)
    3 / 50 (6.00%)
    21 / 246 (8.54%)
         occurrences all number
    54
    3
    29
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    21 / 245 (8.57%)
    2 / 50 (4.00%)
    21 / 246 (8.54%)
         occurrences all number
    22
    2
    24
    Cough
         subjects affected / exposed
    41 / 245 (16.73%)
    5 / 50 (10.00%)
    32 / 246 (13.01%)
         occurrences all number
    54
    5
    36
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    23 / 245 (9.39%)
    1 / 50 (2.00%)
    17 / 246 (6.91%)
         occurrences all number
    24
    1
    17
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    19 / 245 (7.76%)
    4 / 50 (8.00%)
    13 / 246 (5.28%)
         occurrences all number
    26
    5
    14
    Blood creatinine increased
         subjects affected / exposed
    24 / 245 (9.80%)
    3 / 50 (6.00%)
    20 / 246 (8.13%)
         occurrences all number
    32
    3
    23
    Aspartate aminotransferase increased
         subjects affected / exposed
    55 / 245 (22.45%)
    3 / 50 (6.00%)
    55 / 246 (22.36%)
         occurrences all number
    98
    3
    83
    Alanine aminotransferase increased
         subjects affected / exposed
    60 / 245 (24.49%)
    3 / 50 (6.00%)
    58 / 246 (23.58%)
         occurrences all number
    96
    5
    82
    Lymphocyte count decreased
         subjects affected / exposed
    16 / 245 (6.53%)
    0 / 50 (0.00%)
    11 / 246 (4.47%)
         occurrences all number
    20
    0
    12
    Neutrophil count decreased
         subjects affected / exposed
    90 / 245 (36.73%)
    2 / 50 (4.00%)
    113 / 246 (45.93%)
         occurrences all number
    236
    2
    282
    Platelet count decreased
         subjects affected / exposed
    49 / 245 (20.00%)
    0 / 50 (0.00%)
    52 / 246 (21.14%)
         occurrences all number
    81
    0
    94
    Weight decreased
         subjects affected / exposed
    24 / 245 (9.80%)
    3 / 50 (6.00%)
    16 / 246 (6.50%)
         occurrences all number
    29
    3
    18
    White blood cell count decreased
         subjects affected / exposed
    71 / 245 (28.98%)
    2 / 50 (4.00%)
    87 / 246 (35.37%)
         occurrences all number
    211
    2
    259
    Nervous system disorders
    Headache
         subjects affected / exposed
    29 / 245 (11.84%)
    0 / 50 (0.00%)
    31 / 246 (12.60%)
         occurrences all number
    32
    0
    33
    Dysgeusia
         subjects affected / exposed
    16 / 245 (6.53%)
    0 / 50 (0.00%)
    6 / 246 (2.44%)
         occurrences all number
    35
    0
    7
    Dizziness
         subjects affected / exposed
    22 / 245 (8.98%)
    1 / 50 (2.00%)
    23 / 246 (9.35%)
         occurrences all number
    42
    1
    38
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    99 / 245 (40.41%)
    4 / 50 (8.00%)
    110 / 246 (44.72%)
         occurrences all number
    161
    4
    177
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 245 (3.67%)
    2 / 50 (4.00%)
    15 / 246 (6.10%)
         occurrences all number
    9
    2
    15
    Nausea
         subjects affected / exposed
    96 / 245 (39.18%)
    4 / 50 (8.00%)
    107 / 246 (43.50%)
         occurrences all number
    242
    4
    237
    Diarrhoea
         subjects affected / exposed
    24 / 245 (9.80%)
    0 / 50 (0.00%)
    18 / 246 (7.32%)
         occurrences all number
    27
    0
    23
    Constipation
         subjects affected / exposed
    81 / 245 (33.06%)
    1 / 50 (2.00%)
    76 / 246 (30.89%)
         occurrences all number
    124
    1
    103
    Vomiting
         subjects affected / exposed
    48 / 245 (19.59%)
    5 / 50 (10.00%)
    44 / 246 (17.89%)
         occurrences all number
    61
    5
    55
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    12 / 245 (4.90%)
    3 / 50 (6.00%)
    14 / 246 (5.69%)
         occurrences all number
    17
    3
    16
    Pruritus
         subjects affected / exposed
    17 / 245 (6.94%)
    3 / 50 (6.00%)
    13 / 246 (5.28%)
         occurrences all number
    18
    3
    15
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    13 / 245 (5.31%)
    0 / 50 (0.00%)
    3 / 246 (1.22%)
         occurrences all number
    25
    0
    4
    Hypothyroidism
         subjects affected / exposed
    14 / 245 (5.71%)
    3 / 50 (6.00%)
    6 / 246 (2.44%)
         occurrences all number
    18
    3
    9
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    10 / 245 (4.08%)
    0 / 50 (0.00%)
    17 / 246 (6.91%)
         occurrences all number
    10
    0
    19
    Back pain
         subjects affected / exposed
    25 / 245 (10.20%)
    3 / 50 (6.00%)
    25 / 246 (10.16%)
         occurrences all number
    36
    3
    29
    Arthralgia
         subjects affected / exposed
    19 / 245 (7.76%)
    4 / 50 (8.00%)
    21 / 246 (8.54%)
         occurrences all number
    20
    4
    22
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 245 (4.49%)
    2 / 50 (4.00%)
    18 / 246 (7.32%)
         occurrences all number
    12
    2
    21
    Urinary tract infection
         subjects affected / exposed
    18 / 245 (7.35%)
    0 / 50 (0.00%)
    13 / 246 (5.28%)
         occurrences all number
    19
    0
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    64 / 245 (26.12%)
    4 / 50 (8.00%)
    61 / 246 (24.80%)
         occurrences all number
    81
    4
    79
    Hyperglycaemia
         subjects affected / exposed
    14 / 245 (5.71%)
    2 / 50 (4.00%)
    18 / 246 (7.32%)
         occurrences all number
    16
    2
    32
    Hypokalaemia
         subjects affected / exposed
    16 / 245 (6.53%)
    3 / 50 (6.00%)
    13 / 246 (5.28%)
         occurrences all number
    25
    3
    19
    Hypoalbuminaemia
         subjects affected / exposed
    11 / 245 (4.49%)
    3 / 50 (6.00%)
    12 / 246 (4.88%)
         occurrences all number
    13
    3
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Sep 2018
    Amendment 3: Updated the Inclusion Criteria regarding creatinine clearance in order to align with regulatory safety labeling for pemetrexed.
    24 Mar 2020
    Amendment 4: Based on better understanding of survival outcomes for this population, planned statistical analyses were modified to relax superiority statistics without the need to alter population size. Part of the changes included removal of the Objective Response Rate-only interim analysis.
    23 Feb 2021
    Amendment 5: The control assumption for the planned Overall Survival analysis was updated to better reflect the characteristics of the population that was actually enrolled. The number and timing of analyses has also been updated based on actual enrollment timing.
    19 Jul 2021
    Amendment 6: The dose modification and toxicity management guidelines for immune-related adverse events (irAEs) were updated.
    11 Oct 2022
    Amendment 7: Text was added to specify that interim analysis 3 would become the final analysis if the observed number of events was too close to the target number of events for final analysis.
    23 Aug 2023
    Amendment 8: Text was added to allow participants to rollover to the extension study (MK-3475-587).

    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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