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    Clinical Trial Results:
    A Randomized, Placebo-Controlled, Double-Blind Phase 3 Study to Evaluate the Efficacy and Safety of Tislelizumab (BGB-A317) in Combination with Chemotherapy as First-Line Treatment in Patients with Unresectable, Locally Advanced Recurrent or Metastatic Esophageal Squamous Cell Carcinoma.

    Summary
    EudraCT number
    		 2018-000587-28
    Trial protocol
    		 DE   GB   FR   BE   ES   PL   CZ   IT   RO  
    Global end of trial date
    22 Aug 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jun 2025
    First version publication date
    19 Jun 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BGB-A317-306
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03783442
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BeiGene
    Sponsor organisation address
    311 Pennington-Rocky Hill Rd, Pennington, NJ, United States, 08534
    Public contact
    BeiGene Clinical Support, BeiGene, Ltd., 1 877-828-5568, clinicaltrials@beigene.com
    Scientific contact
    BeiGene Clinical Support, BeiGene, Ltd., 1 877-828-5568, clinicaltrials@beigene.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Aug 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Aug 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate and compare the overall survival (OS) following treatment with tislelizumab in combination with chemotherapy compared to placebo in combination with chemotherapy when given as first-line treatment in patients with unresectable, locally advanced recurrent or metastatic esophageal squamous cell carcinoma (ESCC).
    Protection of trial subjects
    This study was conducted in accordance with BeiGene procedures, which comply with the principles of Good Clinical Practice, International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, the Declaration of Helsinki, and local regulatory requirements. The protocol, any amendments, and informed consent forms (ICFs) were reviewed and approved by the Independent Ethics Committees (IEC)/Institutional Review Board (IRB) in conformance with Good Clinical Practice and applicable regulatory requirements. The IEC/IRB-approved ICF was signed and dated by the patient or the patient’s legally authorized representative before his or her participation in the study. A copy of each signed ICF was provided to the patient or the patient’s legally authorized representative.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Dec 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
    China: 355
    Country: Number of subjects enrolled
    Japan: 66
    Country: Number of subjects enrolled
    Korea, Republic of: 50
    Country: Number of subjects enrolled
    Taiwan: 15
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Russian Federation: 27
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    Czechia: 2
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Italy: 11
    Worldwide total number of subjects
    649
    EEA total number of subjects
    124
    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)
    337
    From 65 to 84 years
    312
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 162 centers in 16 countries/regions across Asia, Europe, North America, and Oceania.

    Pre-assignment
    Screening details
    		 Participants were randomly assigned (1:1) to either tislelizumab plus investigator-chosen chemotherapy (ICC) or placebo plus ICC. Randomization was stratified by ICC (platinum plus fluoropyrimidine vs platinum plus paclitaxel), region (Asia [excluding Japan] vs Japan vs other regions), and previous definitive therapy (yes vs no).

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tislelizumab + Chemotherapy
    Arm description
    		 Participants received tislelizumab 200 mg administered intravenously (IV) on Day 1 of each 3-week treatment cycle together with an investigator-chosen chemotherapy doublet until unacceptable toxicity, disease progression or withdrawal for other reasons.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    BGB-A317
    Other name
    TEVIMBRA®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tislelizumab 200 mg administered by intravenous infusion every 3 weeks.

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Chemotherapy options were a platinum agent (cisplatin 60-80 mg/m² intravenously on Day 1 or oxaliplatin 130 mg/m² intravenously on Day 1) combined with a fluoropyrimidine (fluorouracil [750-800 mg/m² intravenously on Days 1-5] or capecitabine [1000 mg/m² orally twice daily on Days 1-14]) or paclitaxel (175 mg/m² intravenously on Day 1).

    Arm title
    		 Placebo + Chemotherapy
    Arm description
    		 Participants received placebo administered IV on Day 1 of each 3-week treatment cycle together with an investigator-chosen chemotherapy doublet until unacceptable toxicity, disease progression or withdrawal for other reasons.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo to tislelizumab administered by intravenous infusion every 3 weeks

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Chemotherapy options were a platinum agent (cisplatin 60-80 mg/m² intravenously on Day 1 or oxaliplatin 130 mg/m² intravenously on Day 1) combined with a fluoropyrimidine (fluorouracil [750-800 mg/m² intravenously on Days 1-5] or capecitabine [1000 mg/m² orally twice daily on Days 1-14]) or paclitaxel (175 mg/m² intravenously on Day 1).

    Number of subjects in period 1
    		Tislelizumab + Chemotherapy Placebo + Chemotherapy
    Started
    326
    323
    Treated
    324
    321
    Completed
    0
    0
    Not completed
    326
    323
         Consent withdrawn by subject
    19
    21
         Sponsor Ended Study
    48
    28
         Death
    252
    268
         Lost to follow-up
    7
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tislelizumab + Chemotherapy
    Reporting group description
    		 Participants received tislelizumab 200 mg administered intravenously (IV) on Day 1 of each 3-week treatment cycle together with an investigator-chosen chemotherapy doublet until unacceptable toxicity, disease progression or withdrawal for other reasons.

    Reporting group title
    Placebo + Chemotherapy
    Reporting group description
    		 Participants received placebo administered IV on Day 1 of each 3-week treatment cycle together with an investigator-chosen chemotherapy doublet until unacceptable toxicity, disease progression or withdrawal for other reasons.

    Reporting group values
    		 Tislelizumab + Chemotherapy Placebo + Chemotherapy Total
    Number of subjects
    		 326 323 649
    Age categorical
    Units: Subjects
        < 65 years
    		 176 161 337
        ≥ 65 years
    		 150 162 312
    Age continuous
    Units: years
        median (full range (min-max))
    		 64.0 (26 to 84) 65.0 (40 to 84) -
    Gender categorical
    Units: Subjects
        Female
    		 44 42 86
        Male
    		 282 281 563
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 243 243 486
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 79 76 155
        Unknown or Not Reported
    		 4 3 7
    Geographic Region
    Rest of World includes Europe, North America and Oceania.
    Units: Subjects
        Asia (excluding Japan)
    		 210 210 420
        Japan
    		 33 33 66
        Rest of World
    		 83 80 163
    Prior Definitive Therapy
    Units: Subjects
        Yes
    		 152 150 302
        No
    		 174 173 347
    Investigator Chosen Chemotherapy
    Units: Subjects
        Platinum with Fluoropyrimidine
    		 147 146 293
        Platinum with Paclitaxel
    		 179 177 356
    Programmed Cell Death Protein Ligand-1 (PD-L1) Expression
    PD-L1 is a protein found on some normal cells and in higher-than-normal amounts on certain cancer cells that can block the immune system from attacking cancer cells. PD-L1 expression was assessed by a central laboratory using the tumor area positivity (TAP) score, defined as total percentage of tumor area (tumor and any desmoplastic stroma) covered by tumor cells with PD-L1 membrane staining (any intensity), and tumor associated immune cells with PD-L1 staining (any intensity), visually estimated by pathologists using the Ventana PD-L1 (SP263) assay.
    Units: Subjects
        PD-L1 Score ≥ 10%
    		 116 107 223
        PD-L1 Score < 10%
    		 151 168 319
        Unknown
    		 59 48 107

    End points

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    End points reporting groups
    Reporting group title
    Tislelizumab + Chemotherapy
    Reporting group description
    		 Participants received tislelizumab 200 mg administered intravenously (IV) on Day 1 of each 3-week treatment cycle together with an investigator-chosen chemotherapy doublet until unacceptable toxicity, disease progression or withdrawal for other reasons.

    Reporting group title
    Placebo + Chemotherapy
    Reporting group description
    		 Participants received placebo administered IV on Day 1 of each 3-week treatment cycle together with an investigator-chosen chemotherapy doublet until unacceptable toxicity, disease progression or withdrawal for other reasons.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival is defined as the time from the date of randomization until the date of death due to any cause. Median OS was estimated using the Kaplan-Meier method. The Intent-to-Treat (ITT) Analysis Set included all randomized participants.
    End point type
    Primary
    End point timeframe
    From randomization to the primary analysis cutoff date of 28 February 2022; maximum time on follow-up was 3 years and 2 months.
    End point values
    		 Tislelizumab + Chemotherapy Placebo + Chemotherapy
    Number of subjects analysed
    326
    323
    Units: months
        median (confidence interval 95%)
    17.2 (15.8 to 20.1)
    10.6 (9.3 to 12.1)
    Statistical analysis title
    		 Analysis of OS in the ITT Analysis Set
    Statistical analysis description
    The analysis of overall survival was performed using a stratified log-rank test stratified by pooled geographic region, prior definitive therapy and Investigator chemotherapy choice. The stratified Hazard ratio was based on Cox regression model including treatment arm as a covariate and stratified by pooled geographic region (Asia vs. Rest of World), prior definitive therapy and Investigator choice of chemotherapy as strata.
    Comparison groups
    Placebo + Chemotherapy v Tislelizumab + Chemotherapy
    Number of subjects included in analysis
    649
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Stratified Log-rank Test
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.8
    Notes
    [1] - One-sided p-value estimated from log rank test stratified by pooled geographic region, prior definitive therapy and Investigator chemotherapy choice.

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS is defined as the time from the date of randomization to the date of first documentation of disease progression assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Progressive disease is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing nontarget lesions, or the appearance of 1 or more new lesions.
    End point type
    Secondary
    End point timeframe
    From randomization to the primary analysis cutoff date of 28 February 2022; maximum time on follow-up was 3 years and 2 months.
    End point values
    		 Tislelizumab + Chemotherapy Placebo + Chemotherapy
    Number of subjects analysed
    326
    323
    Units: months
        median (confidence interval 95%)
    7.3 (6.9 to 8.3)
    5.6 (4.9 to 6.0)
    Statistical analysis title
    		 Analysis of PFS
    Statistical analysis description
    The stratified Hazard ratio was based on Cox regression model including treatment arm as a covariate and stratified by pooled geographic region (Asia vs. Rest of World), prior definitive therapy and Investigator choice of chemotherapy as strata.
    Comparison groups
    Tislelizumab + Chemotherapy v Placebo + Chemotherapy
    Number of subjects included in analysis
    649
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Stratified Log-rank test
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.75
    Notes
    [2] - One-sided p-value estimated from log rank test stratified by pooled geographic region, prior definitive therapy and Investigator chemotherapy choice.

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR is defined as the percentage of participants whose best overall response (BOR) was complete response (CR) or partial response (PR) assessed by the investigator per RECIST v1.1. Tumor assessments included computed tomography (CT) scans or magnetic resonance imaging (MRI), with preference for CT, of the neck, chest, and abdomen every 6 weeks for the first 48 weeks, then every 9 weeks after 48 weeks. CR: Disappearance of all target and nontarget lesions with no new lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm. PR: Disappearance of all target lesions with persistence of 1 or more nontarget lesion(s), no new lesions, and/or maintenance of tumor marker level above the normal limits, or, at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
    End point type
    Secondary
    End point timeframe
    Response was assessed every 6 weeks for the first 48 weeks, then every 9 weeks thereafter; up to the primary analysis cutoff date of 28 February 2022; maximum time on follow-up was 3 years and 2 months.
    End point values
    		 Tislelizumab + Chemotherapy Placebo + Chemotherapy
    Number of subjects analysed
    326
    323
    Units: percentage of participants
        number (confidence interval 95%)
    63.5 (58.0 to 68.7)
    42.4 (37.0 to 48.0)
    Statistical analysis title
    		 Analysis of ORR
    Statistical analysis description
    The odds ratio was calculated using the Cochran-Mantel-Haenszel method, stratified by pooled geographic region, prior definitive therapy, and Investigator choice of chemotherapy.
    Comparison groups
    Tislelizumab + Chemotherapy v Placebo + Chemotherapy
    Number of subjects included in analysis
    649
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.73
         upper limit
    		 3.27
    Notes
    [3] - Two-sided Cochran-Mantel-Haenszel test was stratified by pooled geographic region, prior definitive therapy, and Investigator choice of chemotherapy.

    Secondary: Overall Survival (OS) in Participants With a PD-L1 Score ≥ 10%

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    End point title
    		 Overall Survival (OS) in Participants With a PD-L1 Score ≥ 10%
    End point description
    OS is defined as the time from the date of randomization until the date of death due to any cause. Median OS was estimated using the Kaplan-Meier method. The analysis included participants in the ITT Analysis Set with PD-L1 score ≥ 10%.
    End point type
    Secondary
    End point timeframe
    From randomization to the primary analysis cutoff date of 28 February 2022; maximum time on follow-up was 3 years and 2 months.
    End point values
    		 Tislelizumab + Chemotherapy Placebo + Chemotherapy
    Number of subjects analysed
    116
    107
    Units: months
        median (confidence interval 95%)
    16.6 (15.3 to 24.4)
    10.0 (8.6 to 13.3)
    Statistical analysis title
    		 Analysis of OS in PD-L1 Score ≥ 10% Subgroup
    Statistical analysis description
    Stratified Hazard ratio was based on Cox regression model including treatment arm as a covariate and stratified by pooled geographic region (Asia vs. Rest of World), prior definitive therapy and Investigator choice of chemotherapy as strata.
    Comparison groups
    Tislelizumab + Chemotherapy v Placebo + Chemotherapy
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0029 [4]
    Method
    		 Stratified Log-rank test
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.87
    Notes
    [4] - One-sided p-value estimated from log rank test stratified by pooled geographic region, prior definitive therapy and Investigator chemotherapy choice.

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR is defined as the time from the first determination of an objective response until the first documentation of progression assessed by the investigator per RECIST v1.1 or death, whichever occurred first. Median DOR was estimated using the Kaplan-Meier method. The analysis includes participants in the ITT Analysis Set with an objective response.
    End point type
    Secondary
    End point timeframe
    From randomization to the primary analysis cutoff date of 28 February 2022; maximum time on follow-up was 3 years and 2 months.
    End point values
    		 Tislelizumab + Chemotherapy Placebo + Chemotherapy
    Number of subjects analysed
    207
    137
    Units: months
        median (confidence interval 95%)
    7.1 (6.1 to 8.1)
    5.7 (4.4 to 7.1)
    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 – Oesophageal Cancer 18 Question Module (QLQ-OES18) Dysphagia, Eating, Reflux, Pain, and Index Scores

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Oesophageal Cancer 18 Question Module (QLQ-OES18) Dysphagia, Eating, Reflux, Pain, and Index Scores
    End point description
    The EORTC-QLQ-OES18 is the specific esophageal symptoms module of the QLQ-C30. QLQ-OES18 is comprised of 18 questions grouped into 4 multi-item subscales: Dysphagia (3 items), Eating (4 items), Reflux (2 items), and Pain (3 items) and 6 single item subscales (trouble swallowing saliva, choking, dry mouth, taste, coughing, and talking). Participants indicate the extent to which they have experienced symptoms on a scale from 1 (Not at all) to 4 (Very much). Scores are calculated as the average of the items that contribute to the scale, then transformed to a scale from 0 to 100. The OES18 index score is calculated as the average of the 4 multi-item subscales and 6 single-item subscales. Higher scores indicate a higher level of symptomatology or problems. The analysis includes participants in the ITT Analysis Set who completed the EORTC QLQ-OES18 at Baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 6 (Week 15)
    End point values
    		 Tislelizumab + Chemotherapy Placebo + Chemotherapy
    Number of subjects analysed
    310
    309
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Dysphagia
    -0.5 (-4.7 to 3.7)
    -4.9 (-9.4 to -0.5)
        Eating
    -0.9 (-3.1 to 1.3)
    -1.5 (-3.8 to 0.9)
        Reflux
    -1.3 (-3.2 to 0.7)
    0.2 (-1.9 to 2.2)
        Pain
    -5.2 (-6.7 to -3.7)
    -3.3 (-4.9 to -1.8)
        Index Score
    -1.0 (-2.2 to 0.3)
    -0.6 (-1.9 to 0.7)
    Statistical analysis title
    		 Analysis of EORTC QLQ-OES18 Dysphagia Score
    Statistical analysis description
    Analysis of Change from Baseline in EORTC QLQ-OES18 Dysphagia Score at Cycle 6 based on a mixed effect model analysis with QLQ-OES18 scores until Cycle 18 as the response variable, and treatment by study visit interaction, Baseline mean score, and randomization stratification factors as covariates.
    Comparison groups
    Tislelizumab + Chemotherapy v Placebo + Chemotherapy
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1372 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 10.3
    Notes
    [5] - Two-sided p-value estimated from a mixed effect model.
    Statistical analysis title
    		 Analysis of EORTC QLQ-OES18 Eating Score
    Statistical analysis description
    Analysis of Change from Baseline in EORTC QLQ-OES18 Eating Score at Cycle 6 based on a mixed effect model analysis with QLQ-OES18 scores until Cycle 18 as the response variable, and treatment by study visit interaction, Baseline mean score, and randomization stratification factors as covariates.
    Comparison groups
    Tislelizumab + Chemotherapy v Placebo + Chemotherapy
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.713 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 3.7
    Notes
    [6] - Two-sided p-value estimated from a mixed effect model.
    Statistical analysis title
    		 Analysis of EORTC QLQ-OES18 Reflux Score
    Statistical analysis description
    Analysis of Change from Baseline in EORTC QLQ-OES18 Reflux Score at Cycle 6 based on a mixed effect model analysis with QLQ-OES18 scores until Cycle 18 as the response variable, and treatment by study visit interaction, Baseline mean score, and randomization stratification factors as covariates.
    Comparison groups
    Tislelizumab + Chemotherapy v Placebo + Chemotherapy
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3001 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 1.3
    Notes
    [7] - Two-sided p-value estimated from a mixed effect model.
    Statistical analysis title
    		 Analysis of EORTC QLQ-OES18 Pain Score
    Statistical analysis description
    Analysis of Change from Baseline in EORTC QLQ-OES18 Pain Score at Cycle 6 based on a mixed effect model analysis with QLQ-OES18 scores until Cycle 18 as the response variable, and treatment by study visit interaction, Baseline mean score, and randomization stratification factors as covariates.
    Comparison groups
    Tislelizumab + Chemotherapy v Placebo + Chemotherapy
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 0.2
    Statistical analysis title
    		 Analysis of EORTC QLQ-OES18 Index Score
    Statistical analysis description
    Analysis of Change from Baseline in EORTC QLQ-OES18 Index Score at Cycle 6 based on a mixed effect model analysis with QLQ-OES18 scores until Cycle 18 as the response variable, and treatment by study visit interaction, Baseline mean score, and randomization stratification factors as covariates.
    Comparison groups
    Tislelizumab + Chemotherapy v Placebo + Chemotherapy
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 1.4

    Secondary: Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30 (QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) and Physical Functioning Scales

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    End point title
    		 Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30 (QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) and Physical Functioning Scales
    End point description
    The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 = Not at all (best) and 4 = Very Much (worst) and 2 global health quality of life (QOL) questions answered on a 7-point scale where 1 = Very poor and 7 = Excellent. Raw scores are transformed to a 0 to 100 scale via linear transformation. Higher scores in GHS and functional scales indicate better quality of life. The analysis includes participants in the ITT Analysis Set who completed the EORTC QLQ-C30 at Baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 6 (Week 15)
    End point values
    		 Tislelizumab + Chemotherapy Placebo + Chemotherapy
    Number of subjects analysed
    310
    309
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Global Health Status/​QOL
    -0.3 (-2.3 to 1.8)
    -3.6 (-5.8 to -1.4)
        Physical Functioning
    -4.8 (-6.6 to -3.0)
    -7.3 (-9.2 to -5.4)
    Statistical analysis title
    		 Analysis of EORTC QLQ-C30 GHS/QoL Score
    Statistical analysis description
    Analysis of Change from Baseline in Global Health Status/QoL at Cycle 6 based on a mixed effect model analysis, with QLQ-C30 scores until Cycle 18 as the response variable, and treatment by study visit interaction, Baseline mean score, and randomization stratification factors as covariates.
    Comparison groups
    Tislelizumab + Chemotherapy v Placebo + Chemotherapy
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 6.2
    Statistical analysis title
    		 Analysis of EORTC QLQ-C30 Physical Functioning
    Statistical analysis description
    Analysis of Change from Baseline in Physical Functioning at Cycle 6 based on a mixed effect model analysis, with QLQ-C30 scores until cycle 18 as the response variable, and treatment by study visit interaction, Baseline mean score, and randomization stratification factors as covariates.
    Comparison groups
    Tislelizumab + Chemotherapy v Placebo + Chemotherapy
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 5.1

    Secondary: Change From Baseline in EORTC QLQ-C30 Fatigue Scale

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    End point title
    		 Change From Baseline in EORTC QLQ-C30 Fatigue Scale
    End point description
    The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 = Not at all (best) and 4 = Very Much (worst) and 2 global health quality of life (QOL) questions answered on a 7-point scale where 1 = Very poor and 7 = Excellent. Raw scores are transformed to a 0 to 100 scale via linear transformation. The fatigue symptom scale includes 3 items and ranges from 0 to 100, where higher scores indicate a higher level of symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 6 (Week 15)
    End point values
    		 Tislelizumab + Chemotherapy Placebo + Chemotherapy
    Number of subjects analysed
    310
    309
    Units: score on a scale
        least squares mean (confidence interval 95%)
    8.0 (5.7 to 10.4)
    9.4 (6.9 to 11.9)
    Statistical analysis title
    		 Analysis of EORTC QLQ-C30 Fatigue Scale
    Statistical analysis description
    Analysis of Change from Baseline in Fatigue at Cycle 6 based on a mixed effect model analysis with QLQ-C30 scores until Cycle 18 as the response variable, and treatment by study visit interaction, Baseline mean score, and randomization stratification factors as covariates.
    Comparison groups
    Tislelizumab + Chemotherapy v Placebo + Chemotherapy
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7
         upper limit
    		 1.9

    Secondary: Change From Baseline in European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) Visual Analog Scale (VAS)

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    End point title
    		 Change From Baseline in European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) Visual Analog Scale (VAS)
    End point description
    The EQ-5D-5L measures health outcomes using a VAS to record a participant's self-rated health on a scale from 0 to 100, where 100 is 'the best health you can imagine' and 0 is 'the worst health you can imagine.' A higher score indicates better health outcomes. The analysis includes participants in the ITT Analysis Set with EQ-5D-5L measurement at both Baseline and Cycle 6.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 6 (Week 15)
    End point values
    		 Tislelizumab + Chemotherapy Placebo + Chemotherapy
    Number of subjects analysed
    221
    196
    Units: score on a scale
        arithmetic mean (standard deviation)
    -1.1 ( 15.82 )
    -3.1 ( 14.01 )
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants Experiencing Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drugs, whether related to study drugs or not. An SAE is any untoward medical occurrence that, at any dose met any of the following criteria: - Resulted in death. - Was life-threatening. - Required hospitalization or prolongation of existing hospitalization. - Resulted in disability/incapacity. - Was a congenital anomaly/birth defect. - Was considered a significant medical AE by the Investigator based on medical judgement. The Safety Analysis Set included all participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 30 days after last dose; maximum time on treatment was 63.5 months.
    End point values
    		 Tislelizumab + Chemotherapy Placebo + Chemotherapy
    Number of subjects analysed
    324
    321
    Units: participants
        Treatment-emergent adverse event
    323
    319
        Serious adverse events
    160
    128
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug to 30 days after last dose, maximum time on treatment was 63.5 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Placebo + Chemotherapy
    Reporting group description
    		 Participants received placebo administered IV on Day 1 of each 3-week treatment cycle together with an investigator-chosen chemotherapy doublet until unacceptable toxicity, disease progression or withdrawal for other reasons.

    Reporting group title
    Tislelizumab + Chemotherapy
    Reporting group description
    		 Participants received tislelizumab 200 mg administered intravenously on Day 1 of each 3-week treatment cycle together with an investigator-chosen chemotherapy doublet until unacceptable toxicity, disease progression or withdrawal for other reasons.

    Serious adverse events
    		 Placebo + Chemotherapy Tislelizumab + Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    128 / 321 (39.88%)
    160 / 324 (49.38%)
         number of deaths (all causes)
    267
    250
         number of deaths resulting from adverse events
    17
    16
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 321 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive lobular breast carcinoma
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myeloproliferative neoplasm
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Venous thrombosis limb
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 321 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iliac artery occlusion
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Accidental death
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 321 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    3 / 321 (0.93%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 321 (1.25%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 3
         deaths causally related to treatment / all
    2 / 4
    0 / 2
    Fatigue
         subjects affected / exposed
    2 / 321 (0.62%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    4 / 321 (1.25%)
    6 / 324 (1.85%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    3 / 321 (0.93%)
    5 / 324 (1.54%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 321 (0.31%)
    4 / 324 (1.23%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 321 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 321 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Oesophagobronchial fistula
         subjects affected / exposed
    1 / 321 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acquired tracheo-oesophageal fistula
         subjects affected / exposed
    3 / 321 (0.93%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asphyxia
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 321 (0.62%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated lung disease
         subjects affected / exposed
    2 / 321 (0.62%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 321 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    4 / 321 (1.25%)
    6 / 324 (1.85%)
         occurrences causally related to treatment / all
    3 / 4
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 321 (0.62%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Respiratory failure
         subjects affected / exposed
    4 / 321 (1.25%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Stridor
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    4 / 321 (1.25%)
    4 / 324 (1.23%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mutism
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 321 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 321 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 321 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    3 / 321 (0.93%)
    4 / 324 (1.23%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    3 / 321 (0.93%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prohormone brain natriuretic peptide increased
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         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
    1 / 321 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic stenosis
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal stenosis
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Unintentional medical device removal
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access site haematoma
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 321 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Prinzmetal angina
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant spinal cord compression
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 321 (0.62%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (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
    6 / 321 (1.87%)
    6 / 324 (1.85%)
         occurrences causally related to treatment / all
    4 / 6
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    4 / 321 (1.25%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    2 / 321 (0.62%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    7 / 321 (2.18%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    8 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 321 (1.56%)
    5 / 324 (1.54%)
         occurrences causally related to treatment / all
    5 / 5
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 321 (0.00%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oesophageal obstruction
         subjects affected / exposed
    2 / 321 (0.62%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 321 (0.00%)
    4 / 324 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (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
    3 / 321 (0.93%)
    7 / 324 (2.16%)
         occurrences causally related to treatment / all
    2 / 3
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    8 / 321 (2.49%)
    17 / 324 (5.25%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    2 / 321 (0.62%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 321 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Ileus
         subjects affected / exposed
    3 / 321 (0.93%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 321 (0.62%)
    5 / 324 (1.54%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal dysplasia
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal fistula
         subjects affected / exposed
    3 / 321 (0.93%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    3 / 321 (0.93%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    1 / 321 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary hypersecretion
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 321 (0.62%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 321 (0.00%)
    5 / 324 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 321 (0.62%)
    4 / 324 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Vomiting
         subjects affected / exposed
    5 / 321 (1.56%)
    7 / 324 (2.16%)
         occurrences causally related to treatment / all
    4 / 5
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    2 / 321 (0.62%)
    7 / 324 (2.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 321 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 321 (0.00%)
    6 / 324 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 321 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular dysfunction
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypopituitarism
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 321 (0.00%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenocorticotropic hormone deficiency
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Immune-mediated arthritis
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 321 (0.62%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Streptococcal sepsis
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 321 (0.62%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    3 / 321 (0.93%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Carbuncle
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium colitis
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (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
    23 / 321 (7.17%)
    19 / 324 (5.86%)
         occurrences causally related to treatment / all
    9 / 23
    9 / 21
         deaths causally related to treatment / all
    1 / 4
    0 / 1
    Post procedural pneumonia
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 321 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Rash pustular
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 321 (0.62%)
    4 / 324 (1.23%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 321 (0.31%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethritis
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (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
    Cachexia
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    2 / 321 (0.62%)
    6 / 324 (1.85%)
         occurrences causally related to treatment / all
    2 / 3
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 321 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hypercalcaemia
         subjects affected / exposed
    2 / 321 (0.62%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 321 (0.31%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    4 / 321 (1.25%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 321 (0.62%)
    6 / 324 (1.85%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 321 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 321 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 321 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Placebo + Chemotherapy Tislelizumab + Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    314 / 321 (97.82%)
    321 / 324 (99.07%)
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    10 / 321 (3.12%)
    7 / 324 (2.16%)
         occurrences all number
    10
    7
    Hypertension
         subjects affected / exposed
    17 / 321 (5.30%)
    21 / 324 (6.48%)
         occurrences all number
    24
    29
    Hypotension
         subjects affected / exposed
    5 / 321 (1.56%)
    14 / 324 (4.32%)
         occurrences all number
    5
    19
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    4 / 321 (1.25%)
    13 / 324 (4.01%)
         occurrences all number
    4
    14
    Fatigue
         subjects affected / exposed
    55 / 321 (17.13%)
    64 / 324 (19.75%)
         occurrences all number
    77
    84
    Malaise
         subjects affected / exposed
    51 / 321 (15.89%)
    40 / 324 (12.35%)
         occurrences all number
    70
    77
    Non-cardiac chest pain
         subjects affected / exposed
    11 / 321 (3.43%)
    11 / 324 (3.40%)
         occurrences all number
    14
    16
    Oedema peripheral
         subjects affected / exposed
    12 / 321 (3.74%)
    14 / 324 (4.32%)
         occurrences all number
    30
    17
    Pyrexia
         subjects affected / exposed
    38 / 321 (11.84%)
    54 / 324 (16.67%)
         occurrences all number
    46
    80
    Asthenia
         subjects affected / exposed
    46 / 321 (14.33%)
    42 / 324 (12.96%)
         occurrences all number
    55
    55
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    38 / 321 (11.84%)
    51 / 324 (15.74%)
         occurrences all number
    45
    62
    Dysphonia
         subjects affected / exposed
    11 / 321 (3.43%)
    5 / 324 (1.54%)
         occurrences all number
    11
    5
    Dyspnoea
         subjects affected / exposed
    14 / 321 (4.36%)
    23 / 324 (7.10%)
         occurrences all number
    16
    24
    Epistaxis
         subjects affected / exposed
    3 / 321 (0.93%)
    10 / 324 (3.09%)
         occurrences all number
    3
    11
    Hiccups
         subjects affected / exposed
    28 / 321 (8.72%)
    23 / 324 (7.10%)
         occurrences all number
    47
    35
    Oropharyngeal pain
         subjects affected / exposed
    4 / 321 (1.25%)
    19 / 324 (5.86%)
         occurrences all number
    4
    20
    Pneumonitis
         subjects affected / exposed
    6 / 321 (1.87%)
    15 / 324 (4.63%)
         occurrences all number
    6
    16
    Productive cough
         subjects affected / exposed
    18 / 321 (5.61%)
    25 / 324 (7.72%)
         occurrences all number
    22
    27
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    26 / 321 (8.10%)
    30 / 324 (9.26%)
         occurrences all number
    34
    36
    Investigations
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    9 / 321 (2.80%)
    18 / 324 (5.56%)
         occurrences all number
    13
    24
    Alanine aminotransferase increased
         subjects affected / exposed
    42 / 321 (13.08%)
    49 / 324 (15.12%)
         occurrences all number
    61
    76
    Amylase increased
         subjects affected / exposed
    19 / 321 (5.92%)
    22 / 324 (6.79%)
         occurrences all number
    27
    43
    Aspartate aminotransferase increased
         subjects affected / exposed
    37 / 321 (11.53%)
    51 / 324 (15.74%)
         occurrences all number
    57
    86
    Blood alkaline phosphatase increased
         subjects affected / exposed
    15 / 321 (4.67%)
    18 / 324 (5.56%)
         occurrences all number
    20
    28
    Blood bilirubin increased
         subjects affected / exposed
    27 / 321 (8.41%)
    27 / 324 (8.33%)
         occurrences all number
    44
    40
    Blood creatine phosphokinase increased
         subjects affected / exposed
    8 / 321 (2.49%)
    13 / 324 (4.01%)
         occurrences all number
    16
    26
    Blood creatinine increased
         subjects affected / exposed
    30 / 321 (9.35%)
    47 / 324 (14.51%)
         occurrences all number
    73
    83
    Blood urea increased
         subjects affected / exposed
    16 / 321 (4.98%)
    24 / 324 (7.41%)
         occurrences all number
    32
    51
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    17 / 321 (5.30%)
    16 / 324 (4.94%)
         occurrences all number
    21
    23
    Lipase increased
         subjects affected / exposed
    17 / 321 (5.30%)
    18 / 324 (5.56%)
         occurrences all number
    25
    24
    Lymphocyte count decreased
         subjects affected / exposed
    28 / 321 (8.72%)
    23 / 324 (7.10%)
         occurrences all number
    65
    57
    Neutrophil count decreased
         subjects affected / exposed
    155 / 321 (48.29%)
    153 / 324 (47.22%)
         occurrences all number
    486
    497
    Platelet count decreased
         subjects affected / exposed
    55 / 321 (17.13%)
    62 / 324 (19.14%)
         occurrences all number
    111
    121
    Weight decreased
         subjects affected / exposed
    91 / 321 (28.35%)
    97 / 324 (29.94%)
         occurrences all number
    112
    125
    Weight increased
         subjects affected / exposed
    13 / 321 (4.05%)
    29 / 324 (8.95%)
         occurrences all number
    13
    39
    White blood cell count decreased
         subjects affected / exposed
    157 / 321 (48.91%)
    143 / 324 (44.14%)
         occurrences all number
    520
    487
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    17 / 321 (5.30%)
    16 / 324 (4.94%)
         occurrences all number
    23
    18
    Dysgeusia
         subjects affected / exposed
    11 / 321 (3.43%)
    12 / 324 (3.70%)
         occurrences all number
    13
    14
    Hypoaesthesia
         subjects affected / exposed
    40 / 321 (12.46%)
    34 / 324 (10.49%)
         occurrences all number
    44
    35
    Neurotoxicity
         subjects affected / exposed
    11 / 321 (3.43%)
    16 / 324 (4.94%)
         occurrences all number
    12
    19
    Paraesthesia
         subjects affected / exposed
    8 / 321 (2.49%)
    15 / 324 (4.63%)
         occurrences all number
    8
    17
    Peripheral sensory neuropathy
         subjects affected / exposed
    62 / 321 (19.31%)
    74 / 324 (22.84%)
         occurrences all number
    81
    82
    Headache
         subjects affected / exposed
    16 / 321 (4.98%)
    18 / 324 (5.56%)
         occurrences all number
    16
    22
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    28 / 321 (8.72%)
    34 / 324 (10.49%)
         occurrences all number
    87
    86
    Coagulopathy
         subjects affected / exposed
    3 / 321 (0.93%)
    13 / 324 (4.01%)
         occurrences all number
    3
    15
    Anaemia
         subjects affected / exposed
    180 / 321 (56.07%)
    193 / 324 (59.57%)
         occurrences all number
    322
    343
    Neutropenia
         subjects affected / exposed
    45 / 321 (14.02%)
    54 / 324 (16.67%)
         occurrences all number
    148
    122
    Thrombocytopenia
         subjects affected / exposed
    24 / 321 (7.48%)
    29 / 324 (8.95%)
         occurrences all number
    36
    43
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    13 / 321 (4.05%)
    15 / 324 (4.63%)
         occurrences all number
    20
    19
    Constipation
         subjects affected / exposed
    101 / 321 (31.46%)
    102 / 324 (31.48%)
         occurrences all number
    130
    141
    Diarrhoea
         subjects affected / exposed
    76 / 321 (23.68%)
    88 / 324 (27.16%)
         occurrences all number
    118
    124
    Dyspepsia
         subjects affected / exposed
    8 / 321 (2.49%)
    13 / 324 (4.01%)
         occurrences all number
    8
    21
    Dysphagia
         subjects affected / exposed
    29 / 321 (9.03%)
    32 / 324 (9.88%)
         occurrences all number
    30
    41
    Gastrooesophageal reflux disease
         subjects affected / exposed
    15 / 321 (4.67%)
    23 / 324 (7.10%)
         occurrences all number
    17
    26
    Nausea
         subjects affected / exposed
    136 / 321 (42.37%)
    122 / 324 (37.65%)
         occurrences all number
    229
    203
    Stomatitis
         subjects affected / exposed
    48 / 321 (14.95%)
    60 / 324 (18.52%)
         occurrences all number
    67
    113
    Vomiting
         subjects affected / exposed
    86 / 321 (26.79%)
    68 / 324 (20.99%)
         occurrences all number
    145
    112
    Abdominal pain
         subjects affected / exposed
    13 / 321 (4.05%)
    25 / 324 (7.72%)
         occurrences all number
    17
    26
    Abdominal distension
         subjects affected / exposed
    14 / 321 (4.36%)
    17 / 324 (5.25%)
         occurrences all number
    19
    29
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    63 / 321 (19.63%)
    61 / 324 (18.83%)
         occurrences all number
    63
    61
    Dry skin
         subjects affected / exposed
    7 / 321 (2.18%)
    12 / 324 (3.70%)
         occurrences all number
    7
    16
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    14 / 321 (4.36%)
    14 / 324 (4.32%)
         occurrences all number
    16
    17
    Pruritus
         subjects affected / exposed
    21 / 321 (6.54%)
    45 / 324 (13.89%)
         occurrences all number
    27
    56
    Rash
         subjects affected / exposed
    24 / 321 (7.48%)
    38 / 324 (11.73%)
         occurrences all number
    30
    53
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    15 / 321 (4.67%)
    33 / 324 (10.19%)
         occurrences all number
    21
    35
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    32 / 321 (9.97%)
    30 / 324 (9.26%)
         occurrences all number
    45
    37
    Back pain
         subjects affected / exposed
    20 / 321 (6.23%)
    23 / 324 (7.10%)
         occurrences all number
    25
    26
    Muscular weakness
         subjects affected / exposed
    7 / 321 (2.18%)
    10 / 324 (3.09%)
         occurrences all number
    8
    12
    Myalgia
         subjects affected / exposed
    22 / 321 (6.85%)
    28 / 324 (8.64%)
         occurrences all number
    29
    42
    Pain in extremity
         subjects affected / exposed
    29 / 321 (9.03%)
    27 / 324 (8.33%)
         occurrences all number
    36
    37
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    3 / 321 (0.93%)
    10 / 324 (3.09%)
         occurrences all number
    3
    11
    Nasopharyngitis
         subjects affected / exposed
    6 / 321 (1.87%)
    10 / 324 (3.09%)
         occurrences all number
    6
    11
    Pneumonia
         subjects affected / exposed
    14 / 321 (4.36%)
    26 / 324 (8.02%)
         occurrences all number
    15
    28
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 321 (5.30%)
    29 / 324 (8.95%)
         occurrences all number
    19
    36
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    124 / 321 (38.63%)
    142 / 324 (43.83%)
         occurrences all number
    195
    205
    Hypercholesterolaemia
         subjects affected / exposed
    7 / 321 (2.18%)
    13 / 324 (4.01%)
         occurrences all number
    21
    27
    Hyperglycaemia
         subjects affected / exposed
    26 / 321 (8.10%)
    33 / 324 (10.19%)
         occurrences all number
    35
    48
    Hyperkalaemia
         subjects affected / exposed
    17 / 321 (5.30%)
    22 / 324 (6.79%)
         occurrences all number
    33
    33
    Hypertriglyceridaemia
         subjects affected / exposed
    13 / 321 (4.05%)
    16 / 324 (4.94%)
         occurrences all number
    28
    37
    Hyperuricaemia
         subjects affected / exposed
    25 / 321 (7.79%)
    27 / 324 (8.33%)
         occurrences all number
    61
    78
    Hypoalbuminaemia
         subjects affected / exposed
    60 / 321 (18.69%)
    75 / 324 (23.15%)
         occurrences all number
    115
    157
    Hypocalcaemia
         subjects affected / exposed
    17 / 321 (5.30%)
    20 / 324 (6.17%)
         occurrences all number
    28
    28
    Hypochloraemia
         subjects affected / exposed
    31 / 321 (9.66%)
    37 / 324 (11.42%)
         occurrences all number
    52
    64
    Hypokalaemia
         subjects affected / exposed
    54 / 321 (16.82%)
    64 / 324 (19.75%)
         occurrences all number
    83
    105
    Hypomagnesaemia
         subjects affected / exposed
    29 / 321 (9.03%)
    31 / 324 (9.57%)
         occurrences all number
    41
    68
    Hyponatraemia
         subjects affected / exposed
    58 / 321 (18.07%)
    73 / 324 (22.53%)
         occurrences all number
    99
    129
    Hypophosphataemia
         subjects affected / exposed
    15 / 321 (4.67%)
    16 / 324 (4.94%)
         occurrences all number
    24
    22
    Hypoproteinaemia
         subjects affected / exposed
    12 / 321 (3.74%)
    14 / 324 (4.32%)
         occurrences all number
    21
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Sep 2018
    Key changes included: • Added a third stratification factor of investigator choice of chemotherapy for randomization. • Revised inclusion criterion to only allow histologically confirmed diagnosis of ESCC but not either histologically or cytologically confirmed ones. • Revised inclusion criteria for patients with HBV and deleted HCV-associated criteria. • Added criteria to exclude patients who recurred after definitive surgery but still amenable to definitive radiation therapy and/or chemoradiotherapy. • Added enrollment guidelines and monitoring measures for Japanese patients prior to opening full enrollment in Japan. • Added treatment guidance that allowed platinum agent being cisplatin or oxaliplatin (except in China and Japan where oxaliplatin was not permitted) and being stopped after 6 cycles per site or investigator preference or per standard practice. • Added the dose delay or modification guidelines for oxaliplatin. • Added eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test) assessed by an appropriate specialist for increased risks of ophthalmologic AEs after receiving PD-1 inhibitors. • Changed imaging of pelvis to imaging of neck, ie made neck a mandatory site for tumor assessment. • Added potential imAEs of myositis/rhabdomyolysis and myocarditis, including laboratory monitoring for these imAEs and evaluation and management guidelines. • Added the follow-up tumor assessment for patients who continued treatment beyond initial disease progression should be performed no more than 6 to 8 weeks after the initial assessment of radiographic disease progression per Regulatory Authorities’ requirement.
    15 Aug 2019
    Key changes included: • Added additional guidance for patients to take a pulmonary function test at screening. • Added 24 months as the treatment duration and the options of whether to keep on treatment when patients complete the 24 months of treatment. • Added new inclusion criterion “Have newly obtained or archival tissue sample available for biomarker assessment.” to require mandatory collection of tumor tissue. • Clarified inclusion criteria to allow the enrollment of patients whose ESCC with adenocarcinoma differentiation < 5% of the viable tumor sample. • Revised exclusion criterion to exclude any patients who had chance to receive definitive surgery or was potentially curable with radiation therapy. • Updated the enrollment guidelines and monitoring measures for Japanese patients. • Revised the overdose definition for tislelizumab with detailed dose limit. • Added a table with the guidance on dose management including the recommended dose reduction level of each chemotherapy drug.
    25 May 2020
    Key changes included: • Increased sample size from 480 to 622. • Added cardiac enzyme monitoring per the latest protocol template update. • Specified that nonserious AEs that were considered unequivocally due to disease progression should not be recorded, however if there was any uncertainty, it should be recorded as an AE. All SAEs and deaths regardless of relatedness to disease progression should be recorded and reported per the latest protocol template update.
    30 Apr 2021
    Key changes included: • Moved BIRC-assessed PFS from a dual primary objective/endpoint to an exploratory objective/endpoint. • Moved BIRC-assessed ORR and BIRC-assessed DOR from secondary endpoints to exploratory endpoints. • Added one secondary objective: OS in the PD-L1 score ≥ 10% subgroup. • Adjusted the timing for the interim analyses of OS. • Defined PFS assessed by the investigator, OS in the PD-L1 score ≥ 10% subgroup, ORR assessed by the investigator, and HRQoL for hierarchical sequential testing with alpha control.
    13 Mar 2024
    Key changes included: • Add description of unblinding and placebo discontinuation of the study after its interim analysis. • Added description of a rollover study so patients who may benefit from tislelizumab could be offered the option to continue treatment after study closeout.

    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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