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    Clinical Trial Results:
    A Randomized, Controlled, Open-label, Global Phase 3 Study Comparing the Efficacy of the anti-PD-1 Antibody BGB-A317 versus Chemotherapy as Second Line Treatment in Patients with Advanced Unresectable/Metastatic Esophageal Squamous Cell Carcinoma

    Summary
    EudraCT number
    		 2017-003699-30
    Trial protocol
    		 DE   FR   ES   IT   GB   BE  
    Global end of trial date
    28 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Nov 2023
    First version publication date
    26 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BGB-A317-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03430843
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ChinaDrugTrials : CTR20171026 , IND: 135699
    Sponsors
    Sponsor organisation name
    BeiGene, Ltd., c/o BeiGene USA, Inc.
    Sponsor organisation address
    1840 Gateway Drive, Third Floor, San Mateo, United States, 94404
    Public contact
    BeiGene Clinical Support, BeiGene, Ltd., clinicaltrials@beigene.com
    Scientific contact
    BeiGene Clinical Support, BeiGene, Ltd., 1 8778285568, 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 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the overall survival (OS) following treatment with BGB-A317 vs. investigator chosen chemotherapy (ICC) when given as second line treatment in patients with advanced unresectable/metastatic Esophageal Squamous Cell Carcinoma (ESCC)
    Protection of trial subjects
    This trial was designed and monitored in accordance with Sponsor procedures, which comply with the ethical principles of GCP as required by the major regulatory authorities, and in accordance with the Declaration of Helsinki. The IEC/IRB-approved ICF was signed and dated by the subject or the subject’s legally authorized representative before his or her participation in the study. A copy of each signed ICF was provided to the subject or the subject’s legally authorized representative. All signed and dated ICFs were retained in each patient’s study file or in the site file. For any updated or revised ICFs, written informed consent was obtained using the IEC/IRB-approved updated/revised ICFs for continued participation in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jan 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
    Spain: 24
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    China: 296
    Country: Number of subjects enrolled
    Taiwan: 27
    Country: Number of subjects enrolled
    Japan: 50
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 31
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    512
    EEA total number of subjects
    88
    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)
    310
    From 65 to 84 years
    201
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 132 study centers in Mainland China, Taiwan, United States, France, Italy, Germany, Spain, Japan, South Korea, Belgium and the United Kingdom.

    Pre-assignment
    Screening details
    		 The study was composed of an initial screening phase (up to 28 days), a treatment phase, a safety follow-up phase (including Safety Follow-up Visit), and a survival follow-up phase.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    randomized, controlled, open-label study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tislelizumab
    Arm description
    		 Tislelizumab 200 mg intravenously (IV) on Day 1 every 21 days until disease progression, unacceptable toxicity, or other discontinuation criteria were met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tislelizumab
    Investigational medicinal product code
    Other name
    BGB-A317
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Solution for infusion
    Dosage and administration details
    Tislelizumab 200 mg administered intravenously once every 3 weeks

    Arm title
    		 Investigator Chosen Chemotherapy (ICC)
    Arm description
    		 Investigator choice of either paclitaxel 135-175 mg /m² on Day 1 IV every 21 days or 80-100 mg/m^2 on a weekly schedule; docetaxel 75 mg/m^2 IV on Day 1 every 21 days; or irinotecan 125 mg/m^2 IV on Days 1 and 8 every 21 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 135-175 mg /m² administered IV given every 21 days, or 80-100mg/m2 administered IV weekly

    Number of subjects in period 1
    		Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Started
    256
    256
    Treated
    255
    240
    Completed
    0
    0
    Not completed
    256
    256
         Consent withdrawn by subject
    5
    14
         Subject Death
    233
    233
         Sponsor Decision
    17
    6
         Lost to follow-up
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tislelizumab
    Reporting group description
    		 Tislelizumab 200 mg intravenously (IV) on Day 1 every 21 days until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

    Reporting group title
    Investigator Chosen Chemotherapy (ICC)
    Reporting group description
    		 Investigator choice of either paclitaxel 135-175 mg /m² on Day 1 IV every 21 days or 80-100 mg/m^2 on a weekly schedule; docetaxel 75 mg/m^2 IV on Day 1 every 21 days; or irinotecan 125 mg/m^2 IV on Days 1 and 8 every 21 days

    Reporting group values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC) Total
    Number of subjects
    		 256 256 512
    Age categorical
    Unit of measure: participants
    Units: Subjects
        <65 years
    		 152 158 310
        > 65 years
    		 104 98 202
    Age continuous
    Mean (Standard Deviation)
    Units: years
        arithmetic mean (standard deviation)
    		 61.8 ( 8.41 ) 61.8 ( 8.02 ) -
    Gender categorical
    Measure Type: Count of Participants
    Units: Subjects
        Female
    		 39 41 80
        Male
    		 217 215 432
    Race
    Units: Subjects
        Asian
    		 201 207 408
        White or Caucasian
    		 53 44 97
        Not Reported
    		 1 0 1
        Unknown
    		 1 2 3
        Black of African American
    		 0 2 2
        Other
    		 0 1 1
    Eastern Cooperative Oncology Group (ECOG) Performance Status Score
    Measure Description: Measure Description: ECOG performance status is used by doctors and researchers to assess how a participant's disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis. 0 = Fully Active (Most Favorable Activity); 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self-Care; 4 = Completely Disabled, No self-care (Least Favorable Activity)
    Units: Subjects
        Zero
    		 66 61 127
        One
    		 190 195 385
    PD-L1 Expression Status
    Measure Description: Programmed death ligand 1 (PD-L1) positive is defined as visually-estimated Combined Positive Score (vCPS) >= 10%, PD-L1 negative is defined as vCPS < 10%, PD-L1 missing refers to the participants without sample collection, not evaluable at baseline, or scored with unqualified sample. Note terminology was updated from vCPS to Tumor Area Positivity (TAP) score in manuscripts.
    Units: Subjects
        vCPS greater than or equal to 10%
    		 80 62 142
        vCPS less than 10%
    		 100 122 222
        Missing
    		 76 72 148

    End points

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    End points reporting groups
    Reporting group title
    Tislelizumab
    Reporting group description
    		 Tislelizumab 200 mg intravenously (IV) on Day 1 every 21 days until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

    Reporting group title
    Investigator Chosen Chemotherapy (ICC)
    Reporting group description
    		 Investigator choice of either paclitaxel 135-175 mg /m² on Day 1 IV every 21 days or 80-100 mg/m^2 on a weekly schedule; docetaxel 75 mg/m^2 IV on Day 1 every 21 days; or irinotecan 125 mg/m^2 IV on Days 1 and 8 every 21 days

    Primary: Overall survival (OS) in the Intent-to-Treat (ITT) Analysis Set

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    End point title
    		 Overall survival (OS) in the Intent-to-Treat (ITT) Analysis Set
    End point description
    OS is defined as the length of time from the date of randomization until the date of death due to any cause in all randomized participants The ITT analysis set included all randomized participants.
    End point type
    Primary
    End point timeframe
    Approximately 2 years and 10 months from date of first randomization
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    256
    256
    Units: Months
        median (confidence interval 95%)
    8.6 (7.5 to 10.4)
    6.3 (5.3 to 7.0)
    Statistical analysis title
    		 Superiority
    Comparison groups
    Tislelizumab v Investigator Chosen Chemotherapy (ICC)
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 1-sided, Log Rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.85

    Secondary: Overall survival (OS) in the PDL-1 Positive Analysis Set

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    End point title
    		 Overall survival (OS) in the PDL-1 Positive Analysis Set
    End point description
    OS is defined as the time from the date of randomization until the date of death due to any cause in the PD-L1 positive population, defined as vCPS ≥10%. The PD-L1 positive population included all randomized participants with tumor PD-L1 vCPS ≥10%.
    End point type
    Secondary
    End point timeframe
    Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    80
    62
    Units: Months
        median (confidence interval 95%)
    10.2 (8.5 to 14.5)
    5.1 (3.8 to 8.2)
    No statistical analyses for this end point

    Secondary: Objective response rate (ORR) in the ITT analysis set

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    End point title
    		 Objective response rate (ORR) in the ITT analysis set
    End point description
    ORR is defined as the percentage of participants who had complete response (CR) or partial response (PR) as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; The ITT analysis set included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    256
    256
    Units: Percentage of Participants
        number (confidence interval 95%)
    20.3 (15.6 to 25.8)
    9.8 (6.4 to 14.1)
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) in the PD-L1 Positive Analysis Set

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    End point title
    		 Overall Response Rate (ORR) in the PD-L1 Positive Analysis Set
    End point description
    ORR is defined as the percentage of participants who had complete response (CR) or partial response (PR) as assessed by the investigator per RECIST v1.1. The PD-L1 positive population is defined as a visually-estimated combined positive score (vCPS) ≥10%
    End point type
    Secondary
    End point timeframe
    Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    80
    62
    Units: Percentage of Participants
        number (confidence interval 95%)
    26.3 (17 to 37.3)
    11.3 (4.7 to 21.9)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) in the ITT Analysis Set

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    End point title
    		 Progression-free Survival (PFS) in the ITT Analysis Set
    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 RECIST v1.1 or death, whichever occurs first; reported for the ITT analysis set. The ITT analysis set included all randomized participants
    End point type
    Secondary
    End point timeframe
    Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    256
    256
    Units: Months
        median (confidence interval 95%)
    1.6 (1.4 to 2.7)
    2.1 (1.5 to 2.7)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) in the PDL-1 Positive Analysis Set

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    End point title
    		 Progression-free Survival (PFS) in the PDL-1 Positive Analysis Set
    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 RECIST v1.1 or death, whichever occurs first; reported for the PDL-1 Positive Analysis Set. The PD-L1 positive population is defined as a visually-estimated combined positive score (vCPS) ≥10%.
    End point type
    Secondary
    End point timeframe
    Up to 2 years and 10 months from date of first randomization
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    80
    62
    Units: Months
        median (confidence interval 95%)
    2.7 (1.5 to 4.2)
    2.3 (1.4 to 3.0)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) in the ITT Analysis Set

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    End point title
    		 Duration of Response (DOR) in the ITT Analysis Set
    End point description
    DOR is defined as the time from the first determination of an objective response until the first documentation of progression as assessed by the investigator per RECIST v1.1, or death, whichever comes first. The ITT analysis set included all randomized participants; only participants with an objective response (CR or PR) were included in this analysis.
    End point type
    Secondary
    End point timeframe
    Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    52
    25
    Units: Months
        median (confidence interval 95%)
    7.1 (4.1 to 11.3)
    4.0 (2.1 to 8.2)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) in the PDL-1 Positive Analysis Set

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    End point title
    		 Duration of Response (DOR) in the PDL-1 Positive Analysis Set
    End point description
    DOR is defined as the time from the first determination of an objective response until the first documentation of progression as assessed by the investigator per RECIST v1.1, or death, whichever comes first. The PD-L1 positive population is defined as a visually estimated combined positive score (vCPS) ≥10%; only participants with an objective response (CR or PR) were included in this analysis.
    End point type
    Secondary
    End point timeframe
    Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    21
    7 [1]
    Units: Months
        median (confidence interval 95%)
    7.1 (2.9 to 13.2)
    5.7 (1.2 to 9999)
    Notes
    [1] - 9999 = Not estimable due to insufficient number of participants with events
    No statistical analyses for this end point

    Secondary: Health-Related Quality of Life (HRQoL) as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C-30) in the ITT analysis set

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    End point title
    		 Health-Related Quality of Life (HRQoL) as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C-30) in the ITT analysis set
    End point description
    Mean change from baseline in EORTC QLQ-C30 index score. The EORTC QLQ-C30 v3.0 is a questionnaire that assesses quality of life of cancer participants. It includes global health status and quality of life questions related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes. The ITT analysis set included all randomized participants; "Overall number of participants analyzed" refers to number of participants evaluable for this outcome measure and "Number analyzed" refers to participants evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    239
    246
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline; n=239; n=246
    16.2 ( 12.28 )
    18.3 ( 13.86 )
        Change at Cycle 6; n=98; n=36
    0.2 ( 8.28 )
    4.8 ( 9.38 )
    No statistical analyses for this end point

    Secondary: HRQoL as Assessed by EORTC QLQ-C30 in the PDL-1 Positive Analysis Set

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    End point title
    		 HRQoL as Assessed by EORTC QLQ-C30 in the PDL-1 Positive Analysis Set
    End point description
    Mean change from baseline in EORTC QLQ-C30 index score. The EORTC QLQ-C30 v3.0 is a questionnaire that assesses quality of life of cancer participants. It includes global health status and quality of life questions related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes. The PD-L1 positive population is defined as a visually estimated combined positive score (vCPS) ≥10%; "Overall number of participants analyzed" refers to number of participants evaluable for this outcome measure and "Number analyzed" refers to participants evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    77
    59
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline; n=77; n=59
    16.8 ( 10.96 )
    18.8 ( 12.02 )
        Change at Cycle 6; n=39; n=9
    0.5 ( 7.39 )
    0.5 ( 4.86 )
    No statistical analyses for this end point

    Secondary: HRQoL as Assessed by EORTC QLQ-Oesophagus Cancer Module (EORTC QLQ-OES18) Reported in ITT Analysis Set

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    End point title
    		 HRQoL as Assessed by EORTC QLQ-Oesophagus Cancer Module (EORTC QLQ-OES18) Reported in ITT Analysis Set
    End point description
    Mean change from baseline in EORTC QLQ-OES18 index score. The EORTC QLQ-OES18 is a questionnaire that assesses overall symptoms in esophageal cancer participants. It includes questions related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes. The ITT analysis set included all randomized participants; “Overall number of participants analyzed” refers to number of participants evaluable for this outcome measure and “Number analyzed” refers to participants evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline to Cycle 6 Day 1 (each cycle is 21 days)
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    239
    246
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    14.7 ( 11.81 )
    16.3 ( 13.20 )
        Change at Cycle 6
    -0.6 ( 8.63 )
    3.0 ( 12.05 )
    No statistical analyses for this end point

    Secondary: HRQoL as Assessed by EORTC QLQ-OES18) in the PDL-1 Positive Analysis Set.

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    End point title
    		 HRQoL as Assessed by EORTC QLQ-OES18) in the PDL-1 Positive Analysis Set.
    End point description
    Mean change from baseline in EORTC QLQ-OES18 index score. The EORTC QLQ-OES18 is a questionnaire that assesses overall symptoms in esophageal cancer participants. It includes questions related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes. The PD-L1 positive population is defined as a visually-estimated combined positive score (vCPS) ≥10%; “Overall number of participants analyzed” refers to number of participants evaluable for this outcome measure and “Number analyzed” refers to participants evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline to Cycle 6 Day 1 (each cycle is 21 days)
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    76
    59
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    16.5 ( 12.69 )
    18.1 ( 12.21 )
        Change at Cycle 6
    -0.9 ( 7.45 )
    -2.9 ( 5.16 )
    No statistical analyses for this end point

    Secondary: HRQoL as Assessed by European Quality of Life 5-Dimensions 5-Level Questionnaire (EQ-5D-5L) in the ITT Analysis Set

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    End point title
    		 HRQoL as Assessed by European Quality of Life 5-Dimensions 5-Level Questionnaire (EQ-5D-5L) in the ITT Analysis Set
    End point description
    Mean change from baseline in EQ-5D-5L visual acuity score (VAS). 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 ITT analysis set included all randomized participants; “Overall number of participants analyzed” refers to number of participants evaluable for this outcome measure and “Number analyzed” refers to participants evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    242
    247
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    73.7 ( 17.05 )
    72.5 ( 18.13 )
        Change at Cycle 6
    -0.6 ( 14.81 )
    -5.9 ( 16.34 )
    No statistical analyses for this end point

    Secondary: HRQoL as Assessed by EQ-5D-5L in the PD-L1 Positive Analysis Set

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    End point title
    		 HRQoL as Assessed by EQ-5D-5L in the PD-L1 Positive Analysis Set
    End point description
    Mean change from baseline in EQ-5D-5L visual acuity score (VAS). 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 PD-L1 positive population is defined as a visually-estimated combined positive score (vCPS) ≥10%; “Overall number of participants analyzed” refers to number of participants evaluable for this outcome measure and “Number analyzed” refers to participants evaluable at the specified time point
    End point type
    Secondary
    End point timeframe
    Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    78
    59
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    74.1 ( 14.84 )
    70.5 ( 18.40 )
        Change at Cycle 6
    -0.5 ( 17.59 )
    4.4 ( 12.82 )
    No statistical analyses for this end point

    Secondary: Number of participants experiencing adverse events (AEs)

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    End point title
    		 Number of participants experiencing adverse events (AEs)
    End point description
    Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), which includes laboratory tests, physical exams, electrocardiogram results and vital signs
    End point type
    Secondary
    End point timeframe
    From the first dose date to 30 days after the last dose date; up to approximately 4 years and 11 months
    End point values
    		 Tislelizumab Investigator Chosen Chemotherapy (ICC)
    Number of subjects analysed
    255
    240
    Units: Number of Participants
        Number of participants with TEAEs
    245
    236
        Number of participants with SAEs
    109
    106
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality and adverse events (AEs): up to approximately 4 years and 11 months
    Adverse event reporting additional description
    AEs are defined as events that had an onset date or a worsening in severity from baseline (pretreatment) on or after the first dose of study treatment up to 30 days following study treatment discontinuation or initiation of a new anticancer therapy, whichever occurred first.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Investigator Chosen Therapy (ICC)
    Reporting group description
    		 Investigator choice of either paclitaxel 135-175 mg /m² on Day 1 IV every 21 days or 80-100 mg/m^2 on a weekly schedule; docetaxel 75 mg/m^2 IV on Day 1 every 21 days; or irinotecan 125 mg/m^2 IV on Days 1 and 8 every 21 days

    Reporting group title
    Tislelizumab
    Reporting group description
    		 Tislelizumab 200 mg intravenously (IV) on Day 1 every 21 days until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

    Serious adverse events
    		 Investigator Chosen Therapy (ICC) Tislelizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    106 / 240 (44.17%)
    109 / 255 (42.75%)
         number of deaths (all causes)
    233
    233
         number of deaths resulting from adverse events
    28
    35
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 240 (0.42%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    2 / 240 (0.83%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Tumour fistulisation
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour compression
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to heart
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         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 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 240 (1.67%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    1 / 4
    0 / 2
    Fatigue
         subjects affected / exposed
    0 / 240 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    4 / 240 (1.67%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 3
         deaths causally related to treatment / all
    2 / 5
    0 / 3
    Malaise
         subjects affected / exposed
    2 / 240 (0.83%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 240 (0.42%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    1 / 1
    1 / 4
    Oedema peripheral
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 240 (0.83%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 255 (0.39%)
         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
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 240 (0.42%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemoptysis
         subjects affected / exposed
    2 / 240 (0.83%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Immune-mediated lung disease
         subjects affected / exposed
    0 / 240 (0.00%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophagobronchial fistula
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pleural effusion
         subjects affected / exposed
    4 / 240 (1.67%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 240 (0.83%)
    5 / 255 (1.96%)
         occurrences causally related to treatment / all
    1 / 2
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    6 / 6
    Acquired tracheo-oesophageal fistula
         subjects affected / exposed
    4 / 240 (1.67%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchiectasis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pulmonary embolism
         subjects affected / exposed
    1 / 240 (0.42%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 240 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Tracheal stenosis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal fistula
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    8 / 240 (3.33%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    11 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neutrophil count decreased
         subjects affected / exposed
    10 / 240 (4.17%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    14 / 14
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal haemorrhage
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheostomy malfunction
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune-mediated myocarditis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Autoimmune myocarditis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Spinal cord compression
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (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
    1 / 240 (0.42%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 240 (1.25%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    5 / 9
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    8 / 240 (3.33%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    9 / 9
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    4 / 240 (1.67%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 240 (0.83%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (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
    8 / 240 (3.33%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric fistula
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    2 / 240 (0.83%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    4 / 240 (1.67%)
    13 / 255 (5.10%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal obstruction
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagomediastinal fistula
         subjects affected / exposed
    0 / 240 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 240 (0.00%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal fistula
         subjects affected / exposed
    1 / 240 (0.42%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Odynophagia
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 240 (1.67%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    1 / 240 (0.42%)
    5 / 255 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Reflux gastritis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 240 (1.67%)
    4 / 255 (1.57%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    1 / 3
    Vomiting
         subjects affected / exposed
    3 / 240 (1.25%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary obstruction
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephroangiosclerosis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenocorticotropic hormone deficiency
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         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
    Muscle spasms
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated myositis
         subjects affected / exposed
    0 / 240 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 240 (0.42%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pathological fracture
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (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
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peritonitis
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 240 (0.83%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular abscess
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    4 / 240 (1.67%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 2
         deaths causally related to treatment / all
    3 / 3
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 240 (0.42%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 240 (0.42%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    17 / 240 (7.08%)
    19 / 255 (7.45%)
         occurrences causally related to treatment / all
    6 / 18
    10 / 24
         deaths causally related to treatment / all
    1 / 3
    2 / 6
    Pneumonia bacterial
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 240 (2.50%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 240 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 240 (0.00%)
    4 / 255 (1.57%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 240 (0.42%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypochloraemia
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 240 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 240 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Investigator Chosen Therapy (ICC) Tislelizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    231 / 240 (96.25%)
    232 / 255 (90.98%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    3 / 240 (1.25%)
    10 / 255 (3.92%)
         occurrences all number
    4
    12
    Vascular disorders
    Hypotension
         subjects affected / exposed
    6 / 240 (2.50%)
    10 / 255 (3.92%)
         occurrences all number
    8
    14
    Hypertension
         subjects affected / exposed
    6 / 240 (2.50%)
    13 / 255 (5.10%)
         occurrences all number
    15
    32
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    33 / 240 (13.75%)
    40 / 255 (15.69%)
         occurrences all number
    42
    56
    Oedema peripheral
         subjects affected / exposed
    11 / 240 (4.58%)
    9 / 255 (3.53%)
         occurrences all number
    13
    12
    Malaise
         subjects affected / exposed
    35 / 240 (14.58%)
    16 / 255 (6.27%)
         occurrences all number
    54
    18
    Fatigue
         subjects affected / exposed
    42 / 240 (17.50%)
    33 / 255 (12.94%)
         occurrences all number
    68
    43
    Asthenia
         subjects affected / exposed
    36 / 240 (15.00%)
    29 / 255 (11.37%)
         occurrences all number
    63
    41
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    28 / 240 (11.67%)
    44 / 255 (17.25%)
         occurrences all number
    30
    56
    Dysphonia
         subjects affected / exposed
    2 / 240 (0.83%)
    8 / 255 (3.14%)
         occurrences all number
    2
    8
    Dyspnoea
         subjects affected / exposed
    19 / 240 (7.92%)
    25 / 255 (9.80%)
         occurrences all number
    23
    29
    Pneumonitis
         subjects affected / exposed
    2 / 240 (0.83%)
    10 / 255 (3.92%)
         occurrences all number
    2
    12
    Productive cough
         subjects affected / exposed
    18 / 240 (7.50%)
    18 / 255 (7.06%)
         occurrences all number
    19
    21
    Haemoptysis
         subjects affected / exposed
    5 / 240 (2.08%)
    10 / 255 (3.92%)
         occurrences all number
    7
    11
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    17 / 240 (7.08%)
    21 / 255 (8.24%)
         occurrences all number
    23
    24
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    19 / 240 (7.92%)
    33 / 255 (12.94%)
         occurrences all number
    22
    49
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 240 (4.58%)
    37 / 255 (14.51%)
         occurrences all number
    13
    55
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 240 (2.08%)
    17 / 255 (6.67%)
         occurrences all number
    10
    26
    Blood bilirubin increased
         subjects affected / exposed
    6 / 240 (2.50%)
    9 / 255 (3.53%)
         occurrences all number
    11
    16
    Blood creatine phosphokinase MB increased
         subjects affected / exposed
    1 / 240 (0.42%)
    11 / 255 (4.31%)
         occurrences all number
    1
    14
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 240 (0.00%)
    10 / 255 (3.92%)
         occurrences all number
    0
    15
    C-reactive protein increased
         subjects affected / exposed
    2 / 240 (0.83%)
    8 / 255 (3.14%)
         occurrences all number
    2
    8
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    8 / 240 (3.33%)
    14 / 255 (5.49%)
         occurrences all number
    10
    23
    Lymphocyte count decreased
         subjects affected / exposed
    22 / 240 (9.17%)
    12 / 255 (4.71%)
         occurrences all number
    36
    21
    Neutrophil count decreased
         subjects affected / exposed
    88 / 240 (36.67%)
    6 / 255 (2.35%)
         occurrences all number
    202
    19
    Platelet count decreased
         subjects affected / exposed
    16 / 240 (6.67%)
    14 / 255 (5.49%)
         occurrences all number
    20
    23
    Weight decreased
         subjects affected / exposed
    45 / 240 (18.75%)
    62 / 255 (24.31%)
         occurrences all number
    55
    101
    White blood cell count decreased
         subjects affected / exposed
    95 / 240 (39.58%)
    11 / 255 (4.31%)
         occurrences all number
    227
    25
    White blood cell count increased
         subjects affected / exposed
    6 / 240 (2.50%)
    12 / 255 (4.71%)
         occurrences all number
    8
    17
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    19 / 240 (7.92%)
    11 / 255 (4.31%)
         occurrences all number
    26
    13
    Peripheral sensory neuropathy
         subjects affected / exposed
    23 / 240 (9.58%)
    2 / 255 (0.78%)
         occurrences all number
    36
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    109 / 240 (45.42%)
    80 / 255 (31.37%)
         occurrences all number
    192
    139
    Thrombocytopenia
         subjects affected / exposed
    10 / 240 (4.17%)
    5 / 255 (1.96%)
         occurrences all number
    13
    7
    Neutropenia
         subjects affected / exposed
    30 / 240 (12.50%)
    2 / 255 (0.78%)
         occurrences all number
    56
    11
    Leukopenia
         subjects affected / exposed
    29 / 240 (12.08%)
    9 / 255 (3.53%)
         occurrences all number
    57
    19
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    45 / 240 (18.75%)
    41 / 255 (16.08%)
         occurrences all number
    60
    46
    Abdominal pain upper
         subjects affected / exposed
    16 / 240 (6.67%)
    9 / 255 (3.53%)
         occurrences all number
    18
    12
    Abdominal pain
         subjects affected / exposed
    22 / 240 (9.17%)
    17 / 255 (6.67%)
         occurrences all number
    27
    20
    Abdominal distension
         subjects affected / exposed
    8 / 240 (3.33%)
    9 / 255 (3.53%)
         occurrences all number
    9
    10
    Stomatitis
         subjects affected / exposed
    14 / 240 (5.83%)
    9 / 255 (3.53%)
         occurrences all number
    21
    10
    Nausea
         subjects affected / exposed
    72 / 240 (30.00%)
    37 / 255 (14.51%)
         occurrences all number
    123
    43
    Gastrooesophageal reflux disease
         subjects affected / exposed
    12 / 240 (5.00%)
    14 / 255 (5.49%)
         occurrences all number
    13
    16
    Dysphagia
         subjects affected / exposed
    17 / 240 (7.08%)
    22 / 255 (8.63%)
         occurrences all number
    22
    23
    Diarrhoea
         subjects affected / exposed
    75 / 240 (31.25%)
    32 / 255 (12.55%)
         occurrences all number
    134
    47
    Vomiting
         subjects affected / exposed
    48 / 240 (20.00%)
    27 / 255 (10.59%)
         occurrences all number
    88
    33
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    42 / 240 (17.50%)
    1 / 255 (0.39%)
         occurrences all number
    46
    1
    Pruritus
         subjects affected / exposed
    11 / 240 (4.58%)
    25 / 255 (9.80%)
         occurrences all number
    13
    34
    Rash
         subjects affected / exposed
    10 / 240 (4.17%)
    23 / 255 (9.02%)
         occurrences all number
    10
    31
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 240 (0.42%)
    8 / 255 (3.14%)
         occurrences all number
    1
    8
    Hypothyroidism
         subjects affected / exposed
    1 / 240 (0.42%)
    30 / 255 (11.76%)
         occurrences all number
    1
    37
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    18 / 240 (7.50%)
    22 / 255 (8.63%)
         occurrences all number
    24
    25
    Back pain
         subjects affected / exposed
    17 / 240 (7.08%)
    28 / 255 (10.98%)
         occurrences all number
    27
    32
    Myalgia
         subjects affected / exposed
    14 / 240 (5.83%)
    8 / 255 (3.14%)
         occurrences all number
    26
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 240 (2.50%)
    9 / 255 (3.53%)
         occurrences all number
    7
    14
    Pneumonia
         subjects affected / exposed
    14 / 240 (5.83%)
    28 / 255 (10.98%)
         occurrences all number
    17
    31
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 240 (4.58%)
    8 / 255 (3.14%)
         occurrences all number
    11
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    80 / 240 (33.33%)
    42 / 255 (16.47%)
         occurrences all number
    102
    53
    Hyperglycaemia
         subjects affected / exposed
    8 / 240 (3.33%)
    17 / 255 (6.67%)
         occurrences all number
    8
    35
    Hyperkalaemia
         subjects affected / exposed
    2 / 240 (0.83%)
    8 / 255 (3.14%)
         occurrences all number
    3
    13
    Hyperuricaemia
         subjects affected / exposed
    11 / 240 (4.58%)
    6 / 255 (2.35%)
         occurrences all number
    19
    13
    Hypoalbuminaemia
         subjects affected / exposed
    30 / 240 (12.50%)
    36 / 255 (14.12%)
         occurrences all number
    44
    51
    Hypocalcaemia
         subjects affected / exposed
    11 / 240 (4.58%)
    8 / 255 (3.14%)
         occurrences all number
    17
    11
    Hypochloraemia
         subjects affected / exposed
    10 / 240 (4.17%)
    6 / 255 (2.35%)
         occurrences all number
    13
    10
    Hypoglycaemia
         subjects affected / exposed
    3 / 240 (1.25%)
    8 / 255 (3.14%)
         occurrences all number
    4
    11
    Hypokalaemia
         subjects affected / exposed
    22 / 240 (9.17%)
    22 / 255 (8.63%)
         occurrences all number
    42
    23
    Hyponatraemia
         subjects affected / exposed
    33 / 240 (13.75%)
    31 / 255 (12.16%)
         occurrences all number
    45
    56
    Hypoproteinaemia
         subjects affected / exposed
    8 / 240 (3.33%)
    13 / 255 (5.10%)
         occurrences all number
    10
    14

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Nov 2017
    Evaluation of objective response rate, progression-free survival, and duration of response using immune-related RECIST was removed because the tool had not been validated. The stratification factors were modified (gender was replaced with ECOG PS score and ICC option) per the request from the US FDA. Alternative paclitaxel and docetaxel treatment regimens were added to provide Japan-specific regimens per the request from the PMDA. Clarified that patients who had received ≥ 2 prior systemic treatments for advanced unresectable or metastatic ESCC were excluded. Management guidance for infusion-related reactions, severe hypersensitivity reactions, flu-like symptoms, and renal function abnormalities were added. The guidance for the immune-mediated adverse event management was modified and updated
    06 Dec 2017
    The requirement of treatment beyond radiographic progression was further clarified per the request from the US FDA. Criteria for dose modification of paclitaxel, docetaxel and irinotecan and permanent discontinuation of chemotherapy regimens were clarified, and dose modifications guidelines for specific adverse events and other toxicities were provided, per request from the US FDA
    08 Nov 2018
    CK (creatine kinase) and CK-MB (creatine kinase cardiac muscle isoenzyme) tests and management guidance were added to monitor the risk of myocarditis more closely. Incorporated the US FDA request of implementing measures to further decrease the potential for viral reactivation: Continuous treatment for 6 months after treatment discontinuation was required for patients with detectable HbsAg or HBV DNA; continuous effective antiviral therapy was required for patients who had detectable HCV and were receiving treatment at screening. The criterion to exclude patients who had a history of anterior organ transplant, including stem-cell allograft, was added per the request from the French National Agency for the Safety of Medicines and Health Products (ANSM). Immune-mediated adverse event management guidelines were updated: “Tislelizumab must be permanently discontinued for any onset of Grade 4 or recurrent Grade 3 immune-mediated adverse events.” A new appendix of “Determining Line of Therapy in ESCC” was added to further clarify the definition of first-line systemic treatment in inclusion criteria, and first-line or front-line systemic treatment was defined as “platinum-based regimen.”
    20 Mar 2020
    Updated the statistical estimation of the sample size to increase the sample size from 450 to 500 and increase target number of death events from 336 to 400, with the following consideration: (1) overall survival HR was adjusted from 0.73 to 0.75 based on recently published results of anti-PD-1 therapies in second-line treatment of ESCC and (2) addition of a dropout rate of 5%. The predefined interim analysis was removed due to the lack of geographically representative population for the analysis, which resulted from the disparity in global enrollment rates. The overall survival in patients with PD-L1 vCPS ≥ 10% was added as the key secondary endpoint of this study to reflect the clinical relevance and importance of the PD-L1 biomarker in ESCC observed in competitors’ published data. (Note: PD-L1 assessment [by VENTANA PD-L1 SP263 CDx Assay] was not started before the key secondary endpoint was added in this protocol amendment, and PD-L1 status of each patient was unknown.)
    20 Jul 2020
    Provided definition of the predefined cutoff for the PD-L1-Positive Analysis Set. Added details for management of Grade 3 myositis/rhabdomyolysis in Appendix 10 of Study 302 Protocol Amendment Version 4.0

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35442766
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