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    Clinical Trial Results:
    A Phase 2, Open-label, Multicenter, Randomized, Multidrug Platform Study of Durvalumab Alone or in Combination with Novel Agents in Subjects with Locally Advanced, Unresectable, Stage III Non-small Cell Lung Cancer (COAST)

    Summary
    EudraCT number
    		 2018-002931-35
    Trial protocol
    		 FR   PT   ES   PL   IT  
    Global end of trial date
    18 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jul 2024
    First version publication date
    25 Jul 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D9108C00001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03822351
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca Clinical Study Information Center
    Sponsor organisation address
    One MedImmune Way, Gaithersburg, United States, 20878
    Public contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, +1 877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, +1 877-240-9479, information.center@astrazeneca.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
    13 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jul 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the antitumor activity of durvalumab alone vs durvalumab in combination with novel agents by calculating the Objective Response rate (ORR) per Response Evaluation Criteria for Solid Tumors version 1.1
    Protection of trial subjects
    Each subject was assigned a SID to ensure that personally identifiable information is kept separate from the study data. Subject data that are relevant to the study, eg, demographic information, physical or mental health condition, diagnosis, comorbidities, laboratory test results, etc will only be collected with the subject’s informed consent. The informed consent form will incorporate (or, in some cases, be accompanied by a separate document incorporating) wording that describes how subject data will be collected, used, and distributed in compliance with relevant data protection and privacy legislation. Data (clinical and biological sample) from this study may be used and may be combined with results from other studies for additional scientific-related research, based on agreement from the subject as defined in the informed consent form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Dec 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    France: 39
    Country: Number of subjects enrolled
    Hong Kong: 6
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Spain: 53
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    United States: 71
    Worldwide total number of subjects
    189
    EEA total number of subjects
    104
    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)
    87
    From 65 to 84 years
    101
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 258 participants were enrolled in 60 study centers across 8 countries worldwide. 69 participants were not randomized (screen failures) and 189 participants were randomized (1:1:1) to receive either durvalumab monotherapy (n=67); or durvalumab + oleclumab (n=60); or durvalumab + monalizumab (n=62).

    Pre-assignment
    Screening details
    		 The first participant was randomized into the study on 3 January 2019 and the last participant was randomized on 6 July 2020. After randomization, 3 participants (1 from each arm) were deemed not eligible and did not receive treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control Arm (durvalumab monotherapy)
    Arm description
    		 Durvalumab 1500 mg IV monotherapy Q4W
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Durvalumab 1500 mg IV monotherapy Q4W

    Arm title
    		 Arm A (durvalumab + oleclumab)
    Arm description
    		 Durvalumab 1500 mg IV Q4W + Oleclumab 3000 mg IV (Q2W for cycles 1 and 2, then Q4W starting cycle 3)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oleclumab
    Investigational medicinal product code
    MEDI9447
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oleclumab 3000 mg IV (Q2W for cycles 1 and 2, then Q4W starting cycle 3)

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Durvalumab 1500 mg IV monotherapy Q4W

    Arm title
    		 Arm B (durvalumab + monalizumab)
    Arm description
    		 Durvalumab 1500 mg IV Q4W + Monalizumab 750 mg IV Q2W
    Arm type
    		 Experimental

    Investigational medicinal product name
    Monalizumab
    Investigational medicinal product code
    IPH2201
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Monalizumab 750 mg IV Q2W

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Durvalumab 1500 mg IV monotherapy Q4W

    Number of subjects in period 1
    		Control Arm (durvalumab monotherapy) Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Started
    67
    60
    62
    Completed
    21
    29
    30
    Not completed
    46
    31
    32
         Consent withdrawn by subject
    10
    4
    6
         Death
    27
    23
    24
         Progressive Disease
    2
    1
    -
         Lost to follow-up
    6
    2
    1
         Not treated
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control Arm (durvalumab monotherapy)
    Reporting group description
    		 Durvalumab 1500 mg IV monotherapy Q4W

    Reporting group title
    Arm A (durvalumab + oleclumab)
    Reporting group description
    		 Durvalumab 1500 mg IV Q4W + Oleclumab 3000 mg IV (Q2W for cycles 1 and 2, then Q4W starting cycle 3)

    Reporting group title
    Arm B (durvalumab + monalizumab)
    Reporting group description
    		 Durvalumab 1500 mg IV Q4W + Monalizumab 750 mg IV Q2W

    Reporting group values
    		 Control Arm (durvalumab monotherapy) Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab) Total
    Number of subjects
    		 67 60 62 189
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 30 29 28 87
        From 65-84 years
    		 37 31 33 101
        85 years and over
    		 0 0 1 1
    Age Continuous
    Units: years
        median (full range (min-max))
    		 66 (46 to 81) 65 (37 to 83) 65 (44 to 87) -
    Sex: Female, Male
    Units: Participants
        Female
    		 22 18 20 60
        Male
    		 45 42 42 129
    Region of Enrollment
    Units: Subjects
        Canada
    		 3 2 1 6
        France
    		 15 19 5 39
        Hong-Kong
    		 1 2 3 6
        Italy
    		 0 3 3 6
        Portugal
    		 3 0 3 6
        Spain
    		 19 12 22 53
        Taiwan
    		 1 0 1 2
        United States
    		 25 22 24 71
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 3 2 8
        Not Hispanic or Latino
    		 63 56 59 178
        Unknown
    		 1 1 1 3
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 1
        Asian
    		 5 4 5 14
        Black or African American
    		 1 5 2 8
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 1
        White
    		 57 47 55 159
        Other
    		 1 2 0 3
        Missing
    		 2 1 0 3
    Subject analysis sets

    Subject analysis set title
    ITT Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-treat (ITT) population included participants who were randomized and were analyzed according to their randomized treatment group

    Subject analysis set title
    As-treated Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The As-treated population included all participants who receive any IP. Participants were analyzed according to the treatment they received

    Subject analysis sets values
    		 ITT Population As-treated Population
    Number of subjects
    189
    186
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    87
    85
        From 65-84 years
    101
    100
        85 years and over
    1
    1
    Age Continuous
    Units: years
        median (full range (min-max))
    65 (37 to 87)
    65 (37 to 87)
    Sex: Female, Male
    Units: Participants
        Female
    60
    59
        Male
    129
    127
    Region of Enrollment
    Units: Subjects
        Canada
    6
    6
        France
    39
    39
        Hong-Kong
    6
    6
        Italy
    6
    6
        Portugal
    6
    6
        Spain
    53
    51
        Taiwan
    2
    2
        United States
    71
    70
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    8
    8
        Not Hispanic or Latino
    178
    175
        Unknown
    3
    3
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    1
    1
        Asian
    14
    14
        Black or African American
    8
    8
        Native Hawaiian or Other Pacific Islander
    1
    1
        White
    159
    156
        Other
    3
    3
        Missing
    3
    3

    End points

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    End points reporting groups
    Reporting group title
    Control Arm (durvalumab monotherapy)
    Reporting group description
    		 Durvalumab 1500 mg IV monotherapy Q4W

    Reporting group title
    Arm A (durvalumab + oleclumab)
    Reporting group description
    		 Durvalumab 1500 mg IV Q4W + Oleclumab 3000 mg IV (Q2W for cycles 1 and 2, then Q4W starting cycle 3)

    Reporting group title
    Arm B (durvalumab + monalizumab)
    Reporting group description
    		 Durvalumab 1500 mg IV Q4W + Monalizumab 750 mg IV Q2W

    Subject analysis set title
    ITT Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-treat (ITT) population included participants who were randomized and were analyzed according to their randomized treatment group

    Subject analysis set title
    As-treated Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The As-treated population included all participants who receive any IP. Participants were analyzed according to the treatment they received

    Primary: Objective Response (OR) rate as a measure of antitumor activity of durvalumab alone vs durvalumab in combination with novel agents

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    End point title
    		 Objective Response (OR) rate as a measure of antitumor activity of durvalumab alone vs durvalumab in combination with novel agents [1]
    End point description
    ORR was defined as the percentage of participants with at least one visit response of Complete Response (CR) or Partial Response (PR) per RECIST 1.1 for target lesions: CR: Disappearance of all target lesions; PR: >=30% decrease in the sum of the longest diameter of target lesions; OR = CR + PR.
    End point type
    Primary
    End point timeframe
    ORR at 16 weeks after randomization is the timing for radiologic assessment of the primary endpoint
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This should not be required for COAST.
    End point values
    		 Control Arm (durvalumab monotherapy) Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Number of subjects analysed
    67
    60
    62
    Units: Percentage of Participants
        number (confidence interval 95%)
    23.9 (14.3 to 35.9)
    35.0 (23.1 to 48.4)
    40.3 (28.1 to 53.6)
    No statistical analyses for this end point

    Secondary: Incidence of Adverse Events as a measure of safety and tolerability of durvalumab alone and in combination with novel agents

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    End point title
    		 Incidence of Adverse Events as a measure of safety and tolerability of durvalumab alone and in combination with novel agents
    End point description
    The secondary endpoint of safety as assessed by the presence of adverse events and serious adverse events
    End point type
    Secondary
    End point timeframe
    From time of informed consent through treatment period (12 months) or up to 3 months post last dose of study treatment
    End point values
    		 Control Arm (durvalumab monotherapy) Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Number of subjects analysed
    66
    59
    61
    Units: Participants
        Participants with any TEAEs
    65
    57
    61
        Participants with any serious TEAEs
    23
    20
    17
    No statistical analyses for this end point

    Secondary: Incidence of clinically significant laboratory values as a measure of safety and tolerability of durvalumab alone and in combination with novel agents

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    End point title
    		 Incidence of clinically significant laboratory values as a measure of safety and tolerability of durvalumab alone and in combination with novel agents
    End point description
    The secondary endpoint of safety as assessed by the presence of Grade 3 or 4 clinical laboratory toxicities (based on NCI-CTCAE v5.0) in chemistry and hematology values observed from treatment initiation up to and including 3 months post end of treatment.
    End point type
    Secondary
    End point timeframe
    From baseline through treatment up to 5 years after first treatment
    End point values
    		 Control Arm (durvalumab monotherapy) Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Number of subjects analysed
    66
    59
    61
    Units: Participants
        Alanine Aminostransferase (U/L) toxicities
    1
    0
    0
        Albumin (g/dL) toxicities
    2
    0
    0
        Amylase (U/L) toxicities
    1
    0
    2
        Aspartate Aminotransferase (U/L) toxicities
    1
    0
    1
        Creatinine (mg/dL) toxicities
    1
    0
    0
        Creatinine Clearance Rate (mL/min) toxicities
    2
    1
    0
        Gamma Glutamyl Transferase (U/L) toxicities
    1
    0
    0
        Any Grade 3 or 4 Hyperkalemia (mEq/L) toxicities
    0
    0
    2
        Hypokalemia (mEq/L) toxicities
    1
    0
    1
        Hypocalcemia (corrected) (mg/dL) toxicities
    1
    0
    0
        Hypernatremia (mEq/L) toxicities
    1
    2
    1
        Lipase (U/L) toxicities
    1
    4
    2
        Hemoglobin increased (g/dL) toxicities
    3
    0
    0
        Lymphocyte count increased (10^3/uL) toxicities
    19
    11
    11
        Platelet count decreased (10^3/uL) toxicities
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Incidence of abnormalities in Vital Signs as a measure of safety and tolerability of durvalumab alone and in combination with novel agents

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    End point title
    		 Incidence of abnormalities in Vital Signs as a measure of safety and tolerability of durvalumab alone and in combination with novel agents
    End point description
    The secondary endpoint of safety as assessed by the presence of abnormal vital signs reported as adverse events from treatment initiation up to and including 3 months post end of treatment.
    End point type
    Secondary
    End point timeframe
    From baseline through treatment up to 5 years after first treatment
    End point values
    		 Control Arm (durvalumab monotherapy) Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Number of subjects analysed
    66
    59
    61
    Units: Participants
        Hypertension
    3
    3
    0
        Hypotension
    2
    0
    3
        Palpitations
    0
    0
    1
        Pyrexia
    6
    8
    10
        Tachycardia
    1
    2
    2
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) as a measure of efficacy of durvalumab alone vs durvalumab in combination with novel agents

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    End point title
    		 Duration of Response (DoR) as a measure of efficacy of durvalumab alone vs durvalumab in combination with novel agents
    End point description
    The duration from the first documentation of a subsequently confirmed OR to the first documentation of a disease progression according to RECIST v1.1 or death due to any cause, whichever occurs first. Only subjects who have achieved OR (confirmed CR or confirmed PR) will be evaluated for DoR
    End point type
    Secondary
    End point timeframe
    From time of first documented response until disease progression or up to a maximum of 5 years after randomization
    End point values
    		 Control Arm (durvalumab monotherapy) Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Number of subjects analysed
    16
    21
    25
    Units: Months
        median (confidence interval 95%)
    99999 (14.1 to 99999)
    29.9 (17.1 to 99999)
    23.0 (10.2 to 99999)
    No statistical analyses for this end point

    Secondary: Disease Control (DC) as a measure of efficacy of durvalumab alone vs durvalumab in combination with novel agents

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    End point title
    		 Disease Control (DC) as a measure of efficacy of durvalumab alone vs durvalumab in combination with novel agents
    End point description
    Disease control rate (DCR) was defined as the proportion of subjects with a BOR of confirmed CR, confirmed PR, or SD (maintained for ≥ 16 weeks) based on RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    From time of randomization until disease progression or up to a maximum of 5 years
    End point values
    		 Control Arm (durvalumab monotherapy) Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Number of subjects analysed
    67
    60
    62
    Units: Percentage of patients
        number (confidence interval 95%)
    58.2 (45.5 to 70.2)
    80.0 (67.7 to 89.2)
    79.0 (66.8 to 88.3)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) as a measure of efficacy of durvalumab alone vs durvalumab in combination with novel agents

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    End point title
    		 Progression-Free Survival (PFS) as a measure of efficacy of durvalumab alone vs durvalumab in combination with novel agents
    End point description
    From randomization until the first documentation of disease progression according to RECIST v1.1 or death due to any cause, whichever occurs first
    End point type
    Secondary
    End point timeframe
    From time of randomization until disease progression or up to a maximum of 5 years
    End point values
    		 Control Arm (durvalumab monotherapy) Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Number of subjects analysed
    67
    60
    62
    Units: Months
        median (confidence interval 95%)
    7.3 (4.0 to 13.8)
    21.1 (10.4 to 30.9)
    19.8 (13.6 to 31.3)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival 12 month landmark rate (PFS-12) as a measure of efficacy of durvalumab alone vs durvalumab in combination with novel agents

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    End point title
    		 Progression-Free Survival 12 month landmark rate (PFS-12) as a measure of efficacy of durvalumab alone vs durvalumab in combination with novel agents
    End point description
    PFS-12 was defined as the percentage of participants who were alive and progression free at 12 months after randomization.
    End point type
    Secondary
    End point timeframe
    PFS at 12 months after randomization
    End point values
    		 Control Arm (durvalumab monotherapy) Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Number of subjects analysed
    67
    60
    62
    Units: Percentage of Participants
        number (confidence interval 95%)
    37.6 (24.7 to 50.4)
    63.5 (49.2 to 74.7)
    73.2 (59.6 to 82.9)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) as a measure of efficacy of durvalumab alone vs durvalumab in combination with novel agents

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    End point title
    		 Overall Survival (OS) as a measure of efficacy of durvalumab alone vs durvalumab in combination with novel agents
    End point description
    OS was defined as the time from the date of randomization until death due to any cause. Assessed until 18-July-2023 data cut-off, providing a follow-up to a maximum of approximately 2 years.
    End point type
    Secondary
    End point timeframe
    From time of randomization until death due to any cause or up to a maximum of 5 years
    End point values
    		 Control Arm (durvalumab monotherapy) Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Number of subjects analysed
    67
    60
    62
    Units: Months
        median (confidence interval 95%)
    40.9 (22.6 to 99999)
    99999 (31.9 to 99999)
    99999 (31.3 to 99999)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics of durvalumab alone and in combination with novel agents

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    End point title
    		 Pharmacokinetics of durvalumab alone and in combination with novel agents
    End point description
    The PK samples for durvalumab were collected at prespecified time points: Cycle 1 Day 1 (pre-dose), Cycle 1 Day 1 (EOI), Cycle 2 Day 1 (pre-dose), Cycle 7 Day 1 (pre-dose), Cycle 11 Day 1 (pre-dose), every 8 weeks follow-up (10 months post Cycle 1 Day 1 only), and every 12 weeks follow-up (Month 15 only).
    End point type
    Secondary
    End point timeframe
    From randomization up to 15 months after first treatment
    End point values
    		 Control Arm (durvalumab monotherapy) Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Number of subjects analysed
    57
    41
    51
    Units: Micrograms per milliliter
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1: End of Infusion
    318.0 ( 199.6 )
    277.4 ( 316.1 )
    223.7 ( 1272 )
        Cycle 2 Day 1: Pre-Dose
    59.7 ( 58.6 )
    68.0 ( 49.9 )
    74.3 ( 40.7 )
        Cycle 7 Day 1: Pre-Dose
    151.6 ( 37.7 )
    127.9 ( 66.4 )
    176.5 ( 45.6 )
        Cycle 11 Day 1: Pre-Dose
    156.7 ( 50.0 )
    146.5 ( 91.3 )
    172.4 ( 40.4 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics of novel agents in combination with durvalumab

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    End point title
    		 Pharmacokinetics of novel agents in combination with durvalumab [2]
    End point description
    The PK samples for oleclumab and monalizumab were collected at prespecified time points: Cycle 1 Day 1 (pre-dose), Cycle 1 Day 1 (EOI), Cycle 2 Day 1 (pre-dose), Cycle 7 Day 1 (pre-dose), Cycle 11 Day 1 (pre-dose), every 8 weeks follow-up (10 months post Cycle 1 Day 1 only), and every 12 weeks follow-up (Month 15 only).
    End point type
    Secondary
    End point timeframe
    From randomization up to 15 months after first treatment
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Because this is only for combination arms
    End point values
    		 Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Number of subjects analysed
    52
    51
    Units: Micrograms per milliliter
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1: End of Infusion
    581.6 ( 210.5 )
    160.0 ( 286.4 )
        Cycle 2 Day 1: Pre-Dose
    216.4 ( 58.6 )
    102.6 ( 39.2 )
        Cycle 7 Day 1: Pre-Dose
    124.5 ( 109.0 )
    194.5 ( 33.8 )
        Cycle 11 Day 1: Pre-Dose
    132.0 ( 166.8 )
    196.2 ( 48.7 )
    No statistical analyses for this end point

    Secondary: Development of detectable Anti-Drug Antibody (ADA) response to durvalumab alone and in combination with novel agents

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    End point title
    		 Development of detectable Anti-Drug Antibody (ADA) response to durvalumab alone and in combination with novel agents
    End point description
    ADA positive post-baseline only was also referred to as treatment-induced ADA positive. Treatment-boosted ADA was defined as baseline positive ADA titer that was boosted to a 4-fold or higher following drug administration. Persistently positive was defined as positive at ≥2 post-baseline assessments (with ≥16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive was defined as having at least 1 post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive.
    End point type
    Secondary
    End point timeframe
    From randomization up to 15 months after first treatment
    End point values
    		 Control Arm (durvalumab monotherapy) Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Number of subjects analysed
    40
    18
    33
    Units: Participants
        ADA positive at any visit (ADA prevalence)
    3
    1
    2
        Treatment-emergent ADA positive (ADA incidence)
    1
    0
    0
        Treatment-boosted ADA
    0
    0
    0
        Treatment-induced ADA
    1
    0
    0
        ADA positive at baseline only
    2
    1
    2
        ADA positive post-baseline and at baseline
    0
    0
    0
        Persistently positive
    1
    0
    0
        Transiently positive
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Development of detectable Anti-Drug Antibody (ADA) response to novel agents in combination with durvalumab

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    End point title
    		 Development of detectable Anti-Drug Antibody (ADA) response to novel agents in combination with durvalumab [3]
    End point description
    ADA positive post-baseline only was also referred to as treatment-induced ADA positive. Treatment-boosted ADA was defined as baseline positive ADA titer that was boosted to a 4-fold or higher following drug administration. Persistently positive was defined as positive at ≥2 post-baseline assessments (with ≥16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive was defined as having at least 1 post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive.
    End point type
    Secondary
    End point timeframe
    From randomization up to 15 months after first treatment
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Because this is only for combination arms
    End point values
    		 Arm A (durvalumab + oleclumab) Arm B (durvalumab + monalizumab)
    Number of subjects analysed
    54
    51
    Units: Participants
        ADA positive at any visit (ADA prevalence)
    0
    1
        Treatment-emergent ADA positive (ADA incidence)
    0
    1
        Treatment-boosted ADA
    0
    0
        Treatment-induced ADA
    0
    1
        ADA positive at baseline only
    0
    0
        ADA positive post-baseline and at baseline
    0
    0
        Persistently positive
    0
    0
        Transiently positive
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs were collected from time of signature of informed consent up to 12 months post Cycle 1 Day 1. Following the first 12 months post Cycle 1 Day 1, AEs and SAEs were collected up to 3 months post last dose of study treatment.
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAEs) are defined as events present at baseline that worsen in intensity after administration of study IP or events absent at baseline that emerge after administration of study IP. All TEAEs that occurred on and after first dose up to 90 days after last dose of IP (any) were summarized.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Control Arm (durvalumab monotherapy)
    Reporting group description
    		 Durvalumab 1500 mg IV monotherapy Q4W

    Reporting group title
    Arm B (durvalumab + monalizumab)
    Reporting group description
    		 Durvalumab 1500 mg IV Q4W + Monalizumab 750 mg IV Q2W

    Reporting group title
    Arm A (durvalumab + oleclumab)
    Reporting group description
    		 Durvalumab 1500 mg IV Q4W + Oleclumab 3000 mg IV (Q2W for cycles 1 and 2, then Q4W starting cycle 3)

    Serious adverse events
    		 Control Arm (durvalumab monotherapy) Arm B (durvalumab + monalizumab) Arm A (durvalumab + oleclumab)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 66 (34.85%)
    17 / 61 (27.87%)
    20 / 59 (33.90%)
         number of deaths (all causes)
    27
    24
    23
         number of deaths resulting from adverse events
    7
    1
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningioma
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchostenosis
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 66 (3.03%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anoxia
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 66 (1.52%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 66 (4.55%)
    2 / 61 (3.28%)
    6 / 59 (10.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    2 / 66 (3.03%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Oesophagobronchial fistula
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radiation pneumonitis
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Spinal fracture
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary valve stenosis
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 66 (3.03%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual acuity reduced
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis membranous
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord infection
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 61 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 66 (7.58%)
    0 / 61 (0.00%)
    4 / 59 (6.78%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periorbital infection
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Control Arm (durvalumab monotherapy) Arm B (durvalumab + monalizumab) Arm A (durvalumab + oleclumab)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 66 (96.97%)
    60 / 61 (98.36%)
    54 / 59 (91.53%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 66 (4.55%)
    0 / 61 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    4
    0
    4
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 66 (1.52%)
    1 / 61 (1.64%)
    3 / 59 (5.08%)
         occurrences all number
    1
    1
    3
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 66 (6.06%)
    5 / 61 (8.20%)
    5 / 59 (8.47%)
         occurrences all number
    5
    5
    6
    Pyrexia
         subjects affected / exposed
    6 / 66 (9.09%)
    9 / 61 (14.75%)
    7 / 59 (11.86%)
         occurrences all number
    8
    10
    8
    Oedema peripheral
         subjects affected / exposed
    3 / 66 (4.55%)
    5 / 61 (8.20%)
    1 / 59 (1.69%)
         occurrences all number
    3
    5
    1
    Fatigue
         subjects affected / exposed
    7 / 66 (10.61%)
    9 / 61 (14.75%)
    7 / 59 (11.86%)
         occurrences all number
    8
    9
    8
    Asthenia
         subjects affected / exposed
    10 / 66 (15.15%)
    15 / 61 (24.59%)
    11 / 59 (18.64%)
         occurrences all number
    11
    16
    12
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    3 / 66 (4.55%)
    1 / 61 (1.64%)
    3 / 59 (5.08%)
         occurrences all number
    3
    2
    4
    Cough
         subjects affected / exposed
    11 / 66 (16.67%)
    26 / 61 (42.62%)
    19 / 59 (32.20%)
         occurrences all number
    12
    29
    22
    Nasal congestion
         subjects affected / exposed
    4 / 66 (6.06%)
    1 / 61 (1.64%)
    0 / 59 (0.00%)
         occurrences all number
    4
    1
    0
    Productive cough
         subjects affected / exposed
    7 / 66 (10.61%)
    5 / 61 (8.20%)
    6 / 59 (10.17%)
         occurrences all number
    7
    6
    9
    Pneumonitis
         subjects affected / exposed
    7 / 66 (10.61%)
    8 / 61 (13.11%)
    6 / 59 (10.17%)
         occurrences all number
    7
    8
    7
    Pleuritic pain
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 61 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    1
    0
    3
    Pleural effusion
         subjects affected / exposed
    2 / 66 (3.03%)
    1 / 61 (1.64%)
    3 / 59 (5.08%)
         occurrences all number
    2
    3
    3
    Dyspnoea
         subjects affected / exposed
    17 / 66 (25.76%)
    14 / 61 (22.95%)
    15 / 59 (25.42%)
         occurrences all number
    21
    18
    20
    Dysphonia
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 61 (1.64%)
    3 / 59 (5.08%)
         occurrences all number
    0
    1
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 66 (10.61%)
    5 / 61 (8.20%)
    3 / 59 (5.08%)
         occurrences all number
    7
    5
    4
    Anxiety
         subjects affected / exposed
    0 / 66 (0.00%)
    6 / 61 (9.84%)
    1 / 59 (1.69%)
         occurrences all number
    0
    6
    1
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    4 / 66 (6.06%)
    1 / 61 (1.64%)
    8 / 59 (13.56%)
         occurrences all number
    7
    1
    14
    Lipase increased
         subjects affected / exposed
    6 / 66 (9.09%)
    5 / 61 (8.20%)
    5 / 59 (8.47%)
         occurrences all number
    11
    5
    6
    Amylase increased
         subjects affected / exposed
    7 / 66 (10.61%)
    5 / 61 (8.20%)
    4 / 59 (6.78%)
         occurrences all number
    13
    7
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 66 (4.55%)
    4 / 61 (6.56%)
    3 / 59 (5.08%)
         occurrences all number
    3
    7
    3
    Blood creatinine increased
         subjects affected / exposed
    4 / 66 (6.06%)
    6 / 61 (9.84%)
    0 / 59 (0.00%)
         occurrences all number
    5
    7
    0
    Injury, poisoning and procedural complications
    Radiation pneumonitis
         subjects affected / exposed
    3 / 66 (4.55%)
    3 / 61 (4.92%)
    5 / 59 (8.47%)
         occurrences all number
    3
    3
    5
    Fall
         subjects affected / exposed
    5 / 66 (7.58%)
    2 / 61 (3.28%)
    0 / 59 (0.00%)
         occurrences all number
    5
    2
    0
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    2 / 66 (3.03%)
    5 / 61 (8.20%)
    1 / 59 (1.69%)
         occurrences all number
    2
    6
    1
    Headache
         subjects affected / exposed
    2 / 66 (3.03%)
    5 / 61 (8.20%)
    4 / 59 (6.78%)
         occurrences all number
    2
    5
    5
    Hypoaesthesia
         subjects affected / exposed
    1 / 66 (1.52%)
    4 / 61 (6.56%)
    0 / 59 (0.00%)
         occurrences all number
    1
    4
    0
    Dizziness
         subjects affected / exposed
    0 / 66 (0.00%)
    5 / 61 (8.20%)
    3 / 59 (5.08%)
         occurrences all number
    0
    6
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 66 (7.58%)
    1 / 61 (1.64%)
    5 / 59 (8.47%)
         occurrences all number
    8
    1
    9
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 66 (1.52%)
    2 / 61 (3.28%)
    3 / 59 (5.08%)
         occurrences all number
    1
    2
    3
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    4 / 66 (6.06%)
    1 / 61 (1.64%)
    1 / 59 (1.69%)
         occurrences all number
    4
    1
    1
    Nausea
         subjects affected / exposed
    8 / 66 (12.12%)
    5 / 61 (8.20%)
    1 / 59 (1.69%)
         occurrences all number
    10
    7
    1
    Abdominal pain
         subjects affected / exposed
    3 / 66 (4.55%)
    2 / 61 (3.28%)
    4 / 59 (6.78%)
         occurrences all number
    3
    2
    4
    Constipation
         subjects affected / exposed
    10 / 66 (15.15%)
    2 / 61 (3.28%)
    4 / 59 (6.78%)
         occurrences all number
    10
    2
    4
    Diarrhoea
         subjects affected / exposed
    7 / 66 (10.61%)
    13 / 61 (21.31%)
    8 / 59 (13.56%)
         occurrences all number
    9
    19
    8
    Dry mouth
         subjects affected / exposed
    0 / 66 (0.00%)
    3 / 61 (4.92%)
    3 / 59 (5.08%)
         occurrences all number
    0
    5
    3
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    4 / 66 (6.06%)
    4 / 61 (6.56%)
    5 / 59 (8.47%)
         occurrences all number
    4
    5
    5
    Rash maculo-papular
         subjects affected / exposed
    0 / 66 (0.00%)
    5 / 61 (8.20%)
    2 / 59 (3.39%)
         occurrences all number
    0
    5
    2
    Pruritus
         subjects affected / exposed
    7 / 66 (10.61%)
    15 / 61 (24.59%)
    10 / 59 (16.95%)
         occurrences all number
    8
    18
    17
    Rash
         subjects affected / exposed
    6 / 66 (9.09%)
    8 / 61 (13.11%)
    9 / 59 (15.25%)
         occurrences all number
    7
    11
    14
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    10 / 66 (15.15%)
    13 / 61 (21.31%)
    8 / 59 (13.56%)
         occurrences all number
    11
    14
    8
    Hyperthyroidism
         subjects affected / exposed
    9 / 66 (13.64%)
    6 / 61 (9.84%)
    7 / 59 (11.86%)
         occurrences all number
    10
    6
    7
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 66 (7.58%)
    5 / 61 (8.20%)
    3 / 59 (5.08%)
         occurrences all number
    6
    6
    3
    Myalgia
         subjects affected / exposed
    3 / 66 (4.55%)
    2 / 61 (3.28%)
    6 / 59 (10.17%)
         occurrences all number
    4
    2
    7
    Back pain
         subjects affected / exposed
    6 / 66 (9.09%)
    9 / 61 (14.75%)
    6 / 59 (10.17%)
         occurrences all number
    6
    9
    6
    Arthralgia
         subjects affected / exposed
    11 / 66 (16.67%)
    11 / 61 (18.03%)
    10 / 59 (16.95%)
         occurrences all number
    15
    14
    10
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    1 / 66 (1.52%)
    4 / 61 (6.56%)
    4 / 59 (6.78%)
         occurrences all number
    1
    4
    4
    Bronchitis
         subjects affected / exposed
    1 / 66 (1.52%)
    1 / 61 (1.64%)
    4 / 59 (6.78%)
         occurrences all number
    1
    1
    9
    Urinary tract infection
         subjects affected / exposed
    2 / 66 (3.03%)
    1 / 61 (1.64%)
    3 / 59 (5.08%)
         occurrences all number
    2
    1
    7
    Pneumonia
         subjects affected / exposed
    5 / 66 (7.58%)
    5 / 61 (8.20%)
    1 / 59 (1.69%)
         occurrences all number
    7
    5
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    4 / 66 (6.06%)
    1 / 61 (1.64%)
    4 / 59 (6.78%)
         occurrences all number
    5
    1
    7
    Hyperglycaemia
         subjects affected / exposed
    2 / 66 (3.03%)
    3 / 61 (4.92%)
    6 / 59 (10.17%)
         occurrences all number
    2
    3
    8
    Hypercalcaemia
         subjects affected / exposed
    3 / 66 (4.55%)
    1 / 61 (1.64%)
    3 / 59 (5.08%)
         occurrences all number
    3
    1
    4
    Decreased appetite
         subjects affected / exposed
    6 / 66 (9.09%)
    5 / 61 (8.20%)
    6 / 59 (10.17%)
         occurrences all number
    6
    6
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    At data cut-off (18-July-2023), the overall median duration of follow-up was 30.1 months, the overall PFS maturity was 60.8% and the OS maturity was 39.7%. The median OS was not reached in the experimental arms A and B.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35452273
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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