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    Clinical Trial Results:
    A Randomized, Double-Blind, Adaptive, Phase II/III Study of GSK3359609 in Combination With Pembrolizumab and 5FU-Platinum Chemotherapy Versus Placebo in Combination With Pembrolizumab Plus 5FU-Platinum Chemotherapy for First-Line Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

    Summary
    EudraCT number
    		 2019-003981-42
    Trial protocol
    		 FR   SE   DK   DE   BE   GB   HU   PL   GR   IT   RO  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 May 2022
    First version publication date
    13 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    209227
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04428333
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, Belgium, B-1330
    Public contact
    GSK Response Center, GlaxoSmithKline, 044 2089-904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 044 2089-904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    27 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Apr 2021
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To evaluate if the addition of GSK3359609 to pembrolizumab in combination with 5FU-platinum based chemotherapy improves the efficacy of the pembrolizumab combination with 5FU-platinum based chemotherapy in participants with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
    Protection of trial subjects
    Not Applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Aug 2020
    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
    Argentina: 4
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Ireland: 6
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Japan: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Romania: 12
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    116
    EEA total number of subjects
    61
    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)
    76
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment in the study stopped post interim safety/efficacy data review after a pre-specified futility analysis of the 209229 trial. Participants discontinued feladilimab/placebo, but treatment with pembrolizumab + chemotherapy will continue until disease progression, death or unacceptable toxicity.

    Pre-assignment
    Screening details
    		 As of cut-off date, 116 participants were enrolled. One participant was incorrectly re-randomized into the study under a new participant ID but contributed once to the analyses in the started population. Another participant was randomized after the data cut off but did not receive feladilimab/placebo and was not included in the started population.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Feladilimab + Pembrolizumab + 5-FU-platinum chemotherapy
    Arm description
    		 Participants were administered feladilimab (humanized anti- ICOS immunoglobulin G4 [IgG4] monoclonal antibody [mAb]) and pembrolizumab (humanized anti-PD-1 IgG4 mAb) as an intravenous (IV) infusion along with 5 Fluorouracil (FU)- platinum chemotherapy (cisplatin OR carboplatin) every 3 weeks (Q3W).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Feladilimab+ Pembrolizumab+ Platinum chemotherapy (cisplatin/carboplatin)+ Fluorouracil (5FU)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants were administered feladilimab first followed by pembrolizumab and thereafter 5FU-platinum chemotherapy intravenously

    Arm title
    		 Placebo + Pembrolizumab + 5-FU-platinum chemotherapy
    Arm description
    		 Participants were administered placebo and pembrolizumab as an IV infusion along with 5 FU-platinum chemotherapy (cisplatin OR carboplatin) Q3W.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo+ Pembrolizumab+ Platinum chemotherapy (cisplatin/carboplatin)+ Fluorouracil (5FU)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants were administered placebo first followed by pembrolizumab and thereafter 5FU-platinum chemotherapy intravenously

    Number of subjects in period 1
    		Feladilimab + Pembrolizumab + 5-FU-platinum chemotherapy Placebo + Pembrolizumab + 5-FU-platinum chemotherapy
    Started
    57
    59
    mITT population
    52
    55
    Completed
    3
    1
    Not completed
    54
    58
         On Study Treatment (Pembrolizumab)
    47
    47
         Physician decision
    2
    -
         Consent withdrawn by subject
    -
    1
         In Follow-Up
    5
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Feladilimab + Pembrolizumab + 5-FU-platinum chemotherapy
    Reporting group description
    		 Participants were administered feladilimab (humanized anti- ICOS immunoglobulin G4 [IgG4] monoclonal antibody [mAb]) and pembrolizumab (humanized anti-PD-1 IgG4 mAb) as an intravenous (IV) infusion along with 5 Fluorouracil (FU)- platinum chemotherapy (cisplatin OR carboplatin) every 3 weeks (Q3W).

    Reporting group title
    Placebo + Pembrolizumab + 5-FU-platinum chemotherapy
    Reporting group description
    		 Participants were administered placebo and pembrolizumab as an IV infusion along with 5 FU-platinum chemotherapy (cisplatin OR carboplatin) Q3W.

    Reporting group values
    		 Feladilimab + Pembrolizumab + 5-FU-platinum chemotherapy Placebo + Pembrolizumab + 5-FU-platinum chemotherapy Total
    Number of subjects
    		 57 59 116
    Age Categorical
    Units:
        18-64 years
    		 37 39 76
        >=65-84 years
    		 20 20 40
    Sex: Female, Male
    Units: Participants
        Female
    		 10 14 24
        Male
    		 47 45 92
    Race/Ethnicity, Customized
    Units: Subjects
        Asian - Central/South Asian Heritage
    		 2 1 3
        Asian - East Asian Heritage
    		 5 7 12
        Asian - Japanese Heritage
    		 2 0 2
        Asian - South East Asian Heritage
    		 2 1 3
        Black or African American
    		 1 0 1
        Missing
    		 2 1 3
        White - White/Caucasian/European Heritage
    		 43 49 92

    End points

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    End points reporting groups
    Reporting group title
    Feladilimab + Pembrolizumab + 5-FU-platinum chemotherapy
    Reporting group description
    		 Participants were administered feladilimab (humanized anti- ICOS immunoglobulin G4 [IgG4] monoclonal antibody [mAb]) and pembrolizumab (humanized anti-PD-1 IgG4 mAb) as an intravenous (IV) infusion along with 5 Fluorouracil (FU)- platinum chemotherapy (cisplatin OR carboplatin) every 3 weeks (Q3W).

    Reporting group title
    Placebo + Pembrolizumab + 5-FU-platinum chemotherapy
    Reporting group description
    		 Participants were administered placebo and pembrolizumab as an IV infusion along with 5 FU-platinum chemotherapy (cisplatin OR carboplatin) Q3W.

    Subject analysis set title
    Feladilimab + pembrolizumab + chemotherapy mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomized participants whether or not randomized intervention was administered, excluding those who were first dosed or randomized after the date of DIL requesting immediate discontinuation of feladilimab/placebo. This analysis set was based on the study intervention to which the participants were randomized.

    Subject analysis set title
    Placebo + pembrolizumab + chemotherapy mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomized participants whether or not randomized intervention was administered, excluding those who were first dosed or randomized after the date of DIL requesting immediate discontinuation of feladilimab/placebo. This analysis set was based on the study intervention to which the participants were randomized.

    Subject analysis set title
    Feladilimab + pembrolizumab + chemotherapy Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized participants who took at least 1 dose of study intervention. Participants were assigned to the actual study intervention group of feladilimab+pembrolizumab if the participants received any dose of feladilimab. Participants were analyzed according to the actual study intervention received.

    Subject analysis set title
    Placebo + pembrolizumab + chemotherapy Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized participants who took at least 1 dose of study intervention. Participants were assigned to the actual study intervention group of feladilimab+pembrolizumab if the participants received any dose of feladilimab. Participants were analyzed according to the actual study intervention received.

    Primary: Overall Survival (OS) in mITT population

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    End point title
    		 Overall Survival (OS) in mITT population
    End point description
    OS was defined as the time from the date of randomization until the date of death due to any cause. Kaplan-Meier estimate for the median OS is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. All randomized participants whether or not randomized intervention was administered, excluding those who were first dosed or randomized after the date of DIL requesting immediate discontinuation of feladilimab /placebo were included in the mITT population. 99999 = The median was not reached at the time of data cut off and the upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
    End point type
    Primary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    52
    55
    Units: Months
        median (confidence interval 95%)
    99999 (5.1 to 99999)
    99999 (4.1 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and Human Papilloma Virus (HPV) status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
    Comparison groups
    Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.74 [2]
    Method
    		 Stratified Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 23.87
    Notes
    [1] - Other
    [2] - Nominal p-value was calculated based on the one sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx).

    Primary: OS in programmed death receptor-ligand 1 (PD-L1) combined positive score (CPS) ≥1 population

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    End point title
    		 OS in programmed death receptor-ligand 1 (PD-L1) combined positive score (CPS) ≥1 population
    End point description
    OS was defined as the time from the date of randomization until the date of death due to any cause. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Kaplan-Meier estimate for the median OS is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method in PD-L1 CPS ≥1 subjects from mITT population. 99999 = The median was not reached at the time of data cut off and the upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
    End point type
    Primary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    49
    52
    Units: Months
        median (confidence interval 95%)
    99999 (5.1 to 99999)
    99999 (4.1 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS≥20 vs 1≤CPS<20) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
    Comparison groups
    Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.74 [4]
    Method
    		 Stratified Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 23.87
    Notes
    [3] - Other
    [4] - Nominal p-value was calculated based on the one sided log-rank test, stratified by stratified by PD-L1 expression (CPS≥20 vs 1≤CPS<20) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx).

    Primary: Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 in mITT population

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    End point title
    		 Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 in mITT population
    End point description
    PFS per RECIST version (v)1.1 was defined as the time from the date of randomization to the date of first documented disease progression or death due to any cause, whichever occurs first. Kaplan-Meier estimate for the median PFS is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. All participants in the mITT population were analyzed.
    End point type
    Primary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    52
    55
    Units: Months
        median (confidence interval 95%)
    5.5 (3.7 to 5.5)
    4.7 (4.7 to 5.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
    Comparison groups
    Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 = 0.284 [6]
    Method
    		 Stratified Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 2.43
    Notes
    [5] - Other
    [6] - Nominal p-value was calculated based on the one-sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx).

    Secondary: PFS per RECIST v1.1 in the PD-L1 CPS ≥1 population

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    End point title
    		 PFS per RECIST v1.1 in the PD-L1 CPS ≥1 population
    End point description
    PFS per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 was defined as the time from the date of randomization to the date of first documented disease progression or death due to any cause, whichever occurs first. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants in the mITT population with PD-L1 CPS ≥1 is presented here. Kaplan-Meier estimate for the median PFS are presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    49
    52
    Units: Months
        median (confidence interval 95%)
    5.5 (3.7 to 5.5)
    4.7 (4.7 to 6.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS≥20 vs 1≤CPS<20) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
    Comparison groups
    Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 = 0.284 [8]
    Method
    		 Stratified Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 2.43
    Notes
    [7] - Other
    [8] - Nominal p-value was calculated based on the one-sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx).

    Secondary: Milestone OS rate at 12, 24 and 36 months in mITT population

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    End point title
    		 Milestone OS rate at 12, 24 and 36 months in mITT population
    End point description
    Milestone OS rate at 12, 24, and 36 months was not evaluated.
    End point type
    Secondary
    End point timeframe
    Months 12, 24 and 36
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [9] - No participant had follow-up duration exceeding 12 months.
    [10] - No participant had follow-up duration exceeding 12 months.
    No statistical analyses for this end point

    Secondary: Milestone OS rate at 12, 24 and 36 months in PD-L1 CPS ≥1 population

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    End point title
    		 Milestone OS rate at 12, 24 and 36 months in PD-L1 CPS ≥1 population
    End point description
    Milestone OS rate at 12, 24, and 36 months was not evaluated. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells.
    End point type
    Secondary
    End point timeframe
    Months 12, 24 and 36
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [11] - No participant had follow-up duration exceeding 12 months.
    [12] - No participant had follow-up duration exceeding 12 months.
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) per RECIST v1.1 in mITT population

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    End point title
    		 Overall Response Rate (ORR) per RECIST v1.1 in mITT population
    End point description
    ORR per RECIST v1.1 was defined as the proportion of the participants who have a complete response (CR) or partial response (PR) as the best overall response per RECIST v1.1 based upon investigator assessment. As a randomized double-blind study in which primary endpoints are OS and PFS, the confirmation of CR and PR was not required. Rate and associated 2-sided 95 percent Exact (Clopper-Pearson) Confidence Intervals are provided for each treatment arm which are unadjusted. All participants in the mITT population were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    52
    55
    Units: Percentage of participants
        number (confidence interval 95%)
    19.2 (9.6 to 32.5)
    23.6 (13.2 to 37.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The comparison between treatment groups was based on the stratified Miettinen & Nurminen method with strata weighting by sample size and a single treatment covariate. Stratification factors included PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
    Comparison groups
    Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.8
         upper limit
    		 11.3

    Secondary: ORR per RECIST v1.1 in PD-L1 CPS ≥1 population

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    End point title
    		 ORR per RECIST v1.1 in PD-L1 CPS ≥1 population
    End point description
    ORR per RECIST v1.1 was defined as the proportion of the participants who have a CR or PR as the best overall response per RECIST v1.1 based upon investigator assessment. As a randomized double-blind study in which primary endpoints are OS and PFS, the confirmation of CR and PR was not required. Rate and associated 2-sided 95 percent Exact (Clopper-Pearson) Confidence Intervals are provided for each treatment arm which are unadjusted. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants in the mITT population with PD-L1 CPS ≥1 are presented here.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    49
    52
    Units: Percentage of participants
        number (confidence interval 95%)
    18.4 (8.8 to 32.0)
    23.1 (12.5 to 36.8)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The comparison between treatment groups was based on the stratified Miettinen & Nurminen method with strata weighting by sample size and a single treatment covariate. Stratification factors included PD-L1 expression (CPS≥20 vs 1≤CPS<20) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
    Comparison groups
    Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -5.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.4
         upper limit
    		 11.3

    Secondary: Disease Control Rate (DCR) per RECIST v1.1 in mITT population

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    End point title
    		 Disease Control Rate (DCR) per RECIST v1.1 in mITT population
    End point description
    DCR per RECIST v1.1 based upon investigator assessment, was defined as the percentage of participants with a best overall response of CR or PR at any time plus stable disease (SD) meeting the minimum time of 15 weeks. A status of SD≥15 weeks will be assigned if the follow-up disease assessment has met the SD criteria at least once after the date of randomization at a minimum of 14 weeks (98 days) considering a one-week visit window. Rate and associated 2-sided 95 percent Exact (Clopper-Pearson) Confidence Intervals are provided for each treatment arm which are unadjusted. All participants in the mITT population were analysed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    52
    55
    Units: Percentage of participants
        median (confidence interval 95%)
    32.7 (20.3 to 47.1)
    36.4 (23.8 to 50.4)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The comparison between treatment groups was based on the stratified Miettinen & Nurminen method with strata weighting by sample size and a single treatment covariate. Stratification factors included PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
    Comparison groups
    Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.2
         upper limit
    		 13.1

    Secondary: DCR per RECIST v1.1 in PD-L1 CPS ≥1 population

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    End point title
    		 DCR per RECIST v1.1 in PD-L1 CPS ≥1 population
    End point description
    DCR per RECIST v1.1 based upon investigator assessment, was defined as the percentage of participants with a best overall response of CR or PR at any time plus SD meeting the minimum time of 15 weeks. A status of SD≥15 weeks will be assigned if the follow-up disease assessment has met the SD criteria at least once after the date of randomization at a minimum of 14 weeks (98 days) considering a one-week visit window. Rate and associated 2-sided 95 percent Exact (Clopper-Pearson) Confidence Intervals are provided for each treatment arm which are unadjusted. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants in the mITT population with PD-L1 CPS ≥1 are presented here.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    49
    52
    Units: Percentage of participants
        number (confidence interval 95%)
    30.6 (18.3 to 45.4)
    34.6 (22.0 to 49.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The comparison between treatment groups was based on the stratified Miettinen & Nurminen method with strata weighting by sample size and a single treatment covariate. Stratification factors included PD-L1 expression (CPS≥20 vs 1≤CPS<20) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
    Comparison groups
    Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -5.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.8
         upper limit
    		 13.3

    Secondary: Duration of Response (DoR) per RECIST v1.1 in mITT population

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    End point title
    		 Duration of Response (DoR) per RECIST v1.1 in mITT population
    End point description
    DoR per RECIST v1.1 is defined as the time from first documented evidence of CR or PR until first documented disease progression per RECIST v1.1 based upon investigator assessment or death due to any cause, whichever occurs first, among participants who demonstrated CR or PR as the best overall response per RECIST v1.1. Kaplan-Meier estimate for the median DoR is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants with a best overall response of CR or PR in mITT population are presented. 99999 = The median was not reached at the time of data cut off, the lower and upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    10
    13
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    2.8 (1.2 to 2.8)
    No statistical analyses for this end point

    Secondary: DoR per RECIST v1.1 in PD-L1 CPS ≥1 population

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    End point title
    		 DoR per RECIST v1.1 in PD-L1 CPS ≥1 population
    End point description
    DoR per RECIST v1.1 is defined as the time from first documented evidence of CR or PR until first documented disease progression per RECIST v1.1 based upon investigator assessment or death due to any cause, whichever occurs first, among participants who demonstrated CR or PR as the best overall response per RECIST v1.1. Kaplan-Meier estimate for the median DoR is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data for participants with a best overall response of CR or PR in mITT population with PD-L1 CPS ≥1 are presented. 99999 = The median was not reached at the time of data cut off, the lower and upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    9
    12
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    2.8 (1.4 to 2.8)
    No statistical analyses for this end point

    Secondary: Number of participants with Adverse Events (AEs) in safety population

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    End point title
    		 Number of participants with Adverse Events (AEs) in safety population
    End point description
    An AE was defined as any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant’s participation in the research, whether or not considered related to the participant’s participation in the research. All participants in the safety population were analysed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    50
    65
    Units: Participants
    49
    59
    No statistical analyses for this end point

    Secondary: Number of participants with Serious Adverse Events (SAEs) in safety population

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    End point title
    		 Number of participants with Serious Adverse Events (SAEs) in safety population
    End point description
    A SAE was defined as any untoward medical occurrence that, at any dose, results in death, was life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, was a congenital anomaly/birth defect and other situations according to medical or scientific judgement. All participants in the safety population were analysed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    50
    65
    Units: Participants
    19
    18
    No statistical analyses for this end point

    Secondary: Number of participants with adverse Events of Special Interest (AESI) in safety population

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    End point title
    		 Number of participants with adverse Events of Special Interest (AESI) in safety population
    End point description
    AESI was defined as events of potential immunologic etiology, including immune-related (ir) Aes. All participants in the safety population were analysed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    50
    65
    Units: Participants
    21
    23
    No statistical analyses for this end point

    Secondary: Number of participants with AEs in PD-L1 CPS ≥1 population

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    End point title
    		 Number of participants with AEs in PD-L1 CPS ≥1 population
    End point description
    An AE was defined as any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant’s participation in the research, whether or not considered related to the participant’s participation in the research in PD-L1 CPS ≥1 participants from safety population. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    47
    62
    Units: Participants
    46
    56
    No statistical analyses for this end point

    Secondary: Number of participants with SAEs in PD-L1 CPS ≥1 population

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    End point title
    		 Number of participants with SAEs in PD-L1 CPS ≥1 population
    End point description
    A SAE was defined as any untoward medical occurrence that, at any dose, results in death, was life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, was a congenital anomaly/birth defect and other situations according to medical or scientific judgement in PD-L1 CPS ≥1 participants from safety population. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    47
    62
    Units: Participants
    17
    18
    No statistical analyses for this end point

    Secondary: Number of participants with AESIs in PD-L1 CPS ≥1 population

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    End point title
    		 Number of participants with AESIs in PD-L1 CPS ≥1 population
    End point description
    AESI was defined as events of potential immunologic etiology, including irAEs in PD-L1 CPS ≥1 participants from safety population. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    47
    62
    Units: Participants
    20
    20
    No statistical analyses for this end point

    Secondary: Severity of AEs in safety population

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    End point title
    		 Severity of AEs in safety population
    End point description
    Severity of each AE was reported during the study and was assigned a grade according to the National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE). AEs severity were graded on a 5-point scale as: 1 = mild; discomfort noticed, but no disruption to daily activity, 2 = moderate; discomfort sufficient to reduce or affect normal daily activity, 3 = severe; inability to work or perform normal daily activity, 4 = life-threatening consequences and 5 = death related to AE. All participants in the safety population were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    50
    65
    Units: Participants
        Grade 1
    5
    10
        Grade 2
    16
    17
        Grade 3
    21
    26
        Grade 4
    5
    6
        Grade 5
    2
    0
    No statistical analyses for this end point

    Secondary: Severity of SAEs in safety population

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    End point title
    		 Severity of SAEs in safety population
    End point description
    Severity of each SAE was reported during the study and was assigned a grade according to the NCI-CTCAE. SAEs severity were graded on a 5-point scale as: 1 = mild; discomfort noticed, but no disruption to daily activity, 2 = moderate; discomfort sufficient to reduce or affect normal daily activity, 3 = severe; inability to work or perform normal daily activity, 4 = life-threatening consequences and 5 = death related to AE. Data of participants experiencing SAEs of Grade >= 3 have been presented. All participants in the safety population were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    50
    65
    Units: Participants
        Grade >= 3
    13
    15
    No statistical analyses for this end point

    Secondary: Severity of AESIs in safety population

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    End point title
    		 Severity of AESIs in safety population
    End point description
    Severity of each AESI was reported during the study and was assigned a grade according to the NCI-CTCAE. AESIs severity were graded on a 5-point scale as: 1 = mild; discomfort noticed, but no disruption to daily activity, 2 = moderate; discomfort sufficient to reduce or affect normal daily activity, 3 = severe; inability to work or perform normal daily activity, 4 = life-threatening consequences and 5 = death related to AE. Data of participants experiencing AESIs of Grade >= 3 has been presented. Data of participants experiencing AESIs of Grade >= 3 have been presented. All participants in the safety population were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    50
    65
    Units: Participants
        Grade >= 3
    3
    2
    No statistical analyses for this end point

    Secondary: Severity of AEs in PD-L1 CPS ≥1 population

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    End point title
    		 Severity of AEs in PD-L1 CPS ≥1 population
    End point description
    Severity for each AE was reported during the study and assigned a grade according to the NCI-CTCAE v5.0. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data of participants with PD-L1 CPS ≥1 from safety population experiencing AEs of Grade ≥ 3 have been presented.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    47
    62
    Units: Participants
        Grade >= 3
    25
    30
    No statistical analyses for this end point

    Secondary: Severity of SAEs in PD-L1 CPS ≥1 population

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    End point title
    		 Severity of SAEs in PD-L1 CPS ≥1 population
    End point description
    Severity for each SAE was reported during the study and assigned a grade according to the NCI-CTCAE v5.0. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data of participants with PD-L1 CPS ≥1 from safety population experiencing SAEs of Grade ≥3 have been presented.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    47
    62
    Units: Participants
        Grade >= 3
    11
    15
    No statistical analyses for this end point

    Secondary: Severity of AESI in PD-L1 CPS ≥1 population

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    End point title
    		 Severity of AESI in PD-L1 CPS ≥1 population
    End point description
    Severity for each AESI was reported during the study and assigned a grade according to the NCI-CTCAE v5.0. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. Data of participants with PD-L1 CPS ≥1 from safety population experiencing AESIs of Grade ≥3 have been presented.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    47
    62
    Units: Participants
        Grade >= 3
    3
    2
    No statistical analyses for this end point

    Secondary: Number of participants with dose modifications in safety population

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    End point title
    		 Number of participants with dose modifications in safety population
    End point description
    Number of participants with dose modifications (including dose interruptions, dose delays, dose reductions and treatment discontinuations) were reported by each interventional component. All participants in the safety population were analyzed. 99999 = The numbers are reported per component and dose reductions were not permitted for feladilimab/placebo/pembrolizumab.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    50
    65
    Units: Participants
        Dose Interruption per component-feladilimab
    0
    99999
        Dose Interruption per component-placebo
    99999
    0
        Dose Interruption per component-pembrolizumab
    0
    0
        Dose Interruption component-carboplatin/cisplatin
    1
    1
        Dose Interruption per component-fluorouracil
    0
    7
        Dose Delays per component-feladilimab
    13
    99999
        Dose Delays per component-placebo
    99999
    12
        Dose Delays per component-pembrolizumab
    13
    13
        Dose Delays by component-carboplatin/cisplatin
    12
    9
        Dose Delays per component-fluorouracil
    9
    10
        Dose Reduction per component- feladilimab
    99999
    99999
        Dose Reduction per component- placebo
    99999
    99999
        Dose Reduction per component- pembrolizumab
    99999
    99999
        Dose Reduction by component-carboplatin/cisplatin
    12
    19
        Dose Reduction per component-fluorouracil
    18
    21
        Treatment Discontinuation - feladilimab/placebo
    50
    56
        Discontinuation per component-pembrolizumab
    10
    15
        Discontinuation by component-carboplatin/cisplatin
    16
    18
        Discontinuation per component- fluorouracil
    13
    18
    No statistical analyses for this end point

    Secondary: Number of participants with dose modifications in PD-L1 CPS ≥1 population

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    End point title
    		 Number of participants with dose modifications in PD-L1 CPS ≥1 population
    End point description
    Number of participants with dose modifications (i.e. interruptions, discontinuations) in the PD-L1 CPS ≥1 population was reported. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. 99999 = The numbers are reported per component and dose reductions were not permitted for feladilimab/placebo/pembrolizumab.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy Safety Placebo + pembrolizumab + chemotherapy Safety
    Number of subjects analysed
    47
    62
    Units: Participants
        Dose Interruptions per component- feladilimab
    0
    99999
        Dose Interruptions per component- placebo
    99999
    0
        Dose Interruptions per component- pembrolizumab
    0
    0
        Dose Interruptions component-carboplatin/cisplatin
    1
    1
        Dose Interruptions per component- fluorouracil
    0
    7
        Dose Delays per component - feladilimab
    12
    99999
        Dose Delays per component - placebo
    99999
    11
        Dose Delays per component - pembrolizumab
    12
    12
        Dose Delays per component-carboplatin/cisplatin
    11
    9
        Dose Delays per component - fluorouracil
    8
    9
        Dose Reductions per component- feladilimab
    99999
    99999
        Dose Reductions per component- placebo
    99999
    99999
        Dose Reductions per component- pembrolizumab
    99999
    99999
        Dose Reductions by component-carboplatin/cisplatin
    11
    16
        Dose Reductions per component-fluorouracil
    16
    19
        Treatment Discontinuations- feladilimab/placebo
    47
    53
        Discontinuations per component - pembrolizumab
    10
    14
        Discontinuation by component-carboplatin/cisplatin
    13
    16
        Discontinuations per component - fluorouracil
    15
    16
    No statistical analyses for this end point

    Secondary: Time to deterioration in pain in mITT population

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    End point title
    		 Time to deterioration in pain in mITT population
    End point description
    TTD in pain is defined as the time from randomization to the first definitive meaningful deterioration from baseline in the European Organization for Research and Treatment of Cancer Item Library(EORTC IL51) Questionnaire pain domain, i.e. an increase from baseline of at least 8.33 observed at all subsequent non-missing visits. The EORTC Quality of Life Questionnaire 35-Item Head and Neck Module (QLQ-H&N35) is a head and neck specific module with multi-item scales. The questionnaire scores for each scale and single-item measure are averaged and transformed linearly to present a score ranging from 0–100. A high score represents a high/healthy level of functioning. Kaplan-Meier estimate for the median TTD is presented, along with associated 95% confidence interval, estimated using the Brookmeyer-Crowley method. All participants in the mITT population were analysed. 99999 = The upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    52
    55
    Units: Months
        median (confidence interval 95%)
    4.4 (2.1 to 4.4)
    2.8 (1.4 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
    Comparison groups
    Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    P-value
    		 = 0.329 [14]
    Method
    		 Stratified Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.71
    Notes
    [13] - Other
    [14] - Nominal p-value was calculated based on the one-sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx).

    Secondary: Time to deterioration in pain in PD-L1 CPS ≥1 populations

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    End point title
    		 Time to deterioration in pain in PD-L1 CPS ≥1 populations
    End point description
    TTD in pain is defined as the time from randomization to the first definitive meaningful deterioration from baseline in the EORTC IL51 pain domain, i.e. an increase from baseline of at least 8.33 observed at all subsequent non-missing visits. The EORTC QLQ-H&N35 is a head and neck specific module with multi-item scales. The mouth pain, swallowing, speech problems, opening mouth, coughing, feeding tube, and trouble with social eating domains were administered and referred to as the EORTC IL51. The questionnaire scores for each scale and single-item measure are averaged and transformed linearly to present a score ranging from 0–100. A high score represents a high/healthy level of functioning. 99999 = The upper limit of the 95% CI was not calculable from the available data at the time of data cut off. Data for participants with PD-L1 CPS ≥1 in the mITT population are presented.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    52
    55
    Units: Months
        median (confidence interval 95%)
    3.4 (1.3 to 4.4)
    2.8 (1.4 to 9999)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
    Comparison groups
    Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 [15]
    P-value
    		 = 0.302 [16]
    Method
    		 Stratified Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.69
    Notes
    [15] - Other
    [16] - Nominal p-value was calculated based on the one-sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx).

    Secondary: Time to deterioration in physical function in mITT population

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    End point title
    		 Time to deterioration in physical function in mITT population
    End point description
    TTD in physical function is defined as the time from randomization to the first definitive meaningful deterioration from baseline in the Physical Function (PF) T-score, i.e. a decrease from baseline of at least 2.4 observed at all subsequent non-missing visits, as measured by the Patient-Reported Outcomes Measurement Information System - Physical Function (PROMIS PF 8c). The PROMIS PF 8c is an 8-item fixed length short form derived from the PROMIS Physical Function item bank. It includes a 5-point scale with three sets of response options. Scores on the PROMIS PF 8c are reported on a T score metric (mean = 50 and SD = 10), with higher scores reflecting better physical functioning. All participants in the mITT population were analyzed. 99999 = The upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    52
    55
    Units: Months
        median (confidence interval 95%)
    2.8 (1.4 to 99999)
    4.3 (2.1 to 5.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
    Comparison groups
    Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 [17]
    P-value
    		 = 0.472 [18]
    Method
    		 Stratified Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 2.11
    Notes
    [17] - Other
    [18] - Nominal p-value was calculated based on the one-sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20 vs. CPS <1) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx).

    Secondary: Time to deterioration in physical function in PD-L1 CPS ≥1 population

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    End point title
    		 Time to deterioration in physical function in PD-L1 CPS ≥1 population
    End point description
    TTD in physical function is defined as the time from randomization to the first definitive meaningful deterioration from baseline in the PF T-score, i.e. a decrease from baseline of at least 2.4 observed at all subsequent non-missing visits, as measured by the PROMIS PF 8c. The PROMIS PF 8c is an 8-item fixed length short form derived from the PROMIS Physical Function item bank. It includes a 5-point scale with three sets of response options. Scores on the PROMIS PF 8c are reported on a T score metric (mean = 50 and SD = 10), with higher scores reflecting better physical functioning. Data are presented for the PD-L1 CPS ≥1 participants from mITT population. CPS was defined as the ratio of the combined number of PD-L1 expressing tumor cells and immune cells (lymphocytes and macrophages) to the total number of viable tumor cells. 99999 = The upper limit of the 95% CI was not calculable from the available data at the time of data cut off.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 months
    End point values
    		 Feladilimab + pembrolizumab + chemotherapy mITT Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects analysed
    49
    52
    Units: Months
        median (confidence interval 95%)
    4.8 (2.1 to 99999)
    4.3 (2.1 to 5.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The hazard ratio and corresponding 2-sided 95% confidence interval was calculated from the cox regression model with Efron's method of tie handling with treatment as a covariate and stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20) and HPV status (positive vs. negative). Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors were combined as the HPV negative group.
    Comparison groups
    Feladilimab + pembrolizumab + chemotherapy mITT v Placebo + pembrolizumab + chemotherapy mITT
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 [19]
    P-value
    		 = 0.335 [20]
    Method
    		 Stratified Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 1.9
    Notes
    [19] - Other
    [20] - Nominal p-value was calculated based on the one-sided log-rank test, stratified by stratified by PD-L1 expression (CPS ≥20 vs. 1≤ CPS <20) and HPV status (oropharynx HPV positive vs oropharynx HPV negative/unknown and non-oropharynx).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All cause mortality, non-SAEs and SAEs were collected from Day 1 to Up to approximately 7 months.
    Adverse event reporting additional description
    Six participants randomized to feladilimab arm, received first dose after the DIL date were re-assigned to placebo arm.1 participant randomized to feladilimab arm, was never dosed and excluded from the safety population. Safety data for participants who continue to receive Pembrolizumab would be updated after study completion.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Placebo + Pembrolizumab + 5-FU-platinum chemotherapy
    Reporting group description
    		 Participants were administered placebo and pembrolizumab as an IV infusion along with 5FU-platinum chemotherapy (cisplatin OR carboplatin) Q3W.

    Reporting group title
    Feladilimab + Pembrolizumab + 5-FU-platinum chemotherapy
    Reporting group description
    		 Participants were administered feladilimab (humanized anti- ICOS IgG4 mAb) and pembrolizumab (humanized anti-PD-1 IgG4 mAb) as an IV infusion along with 5 FU-platinum chemotherapy (cisplatin OR carboplatin) Q3W.

    Serious adverse events
    		 Placebo + Pembrolizumab + 5-FU-platinum chemotherapy Feladilimab + Pembrolizumab + 5-FU-platinum chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 65 (27.69%)
    19 / 50 (38.00%)
         number of deaths (all causes)
    1
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Embedded device
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal obstruction
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 50 (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
    Cervical cord compression
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 50 (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
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperammonaemia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 50 (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 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 50 (2.00%)
         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: 5%
    Non-serious adverse events
    		 Placebo + Pembrolizumab + 5-FU-platinum chemotherapy Feladilimab + Pembrolizumab + 5-FU-platinum chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 65 (84.62%)
    44 / 50 (88.00%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    5 / 65 (7.69%)
    2 / 50 (4.00%)
         occurrences all number
    5
    2
    Neutrophil count decreased
         subjects affected / exposed
    8 / 65 (12.31%)
    8 / 50 (16.00%)
         occurrences all number
    10
    10
    Platelet count decreased
         subjects affected / exposed
    6 / 65 (9.23%)
    3 / 50 (6.00%)
         occurrences all number
    6
    5
    White blood cell count decreased
         subjects affected / exposed
    5 / 65 (7.69%)
    4 / 50 (8.00%)
         occurrences all number
    5
    5
    Weight decreased
         subjects affected / exposed
    3 / 65 (4.62%)
    5 / 50 (10.00%)
         occurrences all number
    3
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 65 (6.15%)
    3 / 50 (6.00%)
         occurrences all number
    4
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 65 (24.62%)
    22 / 50 (44.00%)
         occurrences all number
    23
    24
    Leukopenia
         subjects affected / exposed
    5 / 65 (7.69%)
    3 / 50 (6.00%)
         occurrences all number
    8
    4
    Neutropenia
         subjects affected / exposed
    14 / 65 (21.54%)
    7 / 50 (14.00%)
         occurrences all number
    22
    10
    Thrombocytopenia
         subjects affected / exposed
    9 / 65 (13.85%)
    5 / 50 (10.00%)
         occurrences all number
    12
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    17 / 65 (26.15%)
    11 / 50 (22.00%)
         occurrences all number
    17
    12
    Asthenia
         subjects affected / exposed
    4 / 65 (6.15%)
    6 / 50 (12.00%)
         occurrences all number
    5
    6
    Mucosal inflammation
         subjects affected / exposed
    14 / 65 (21.54%)
    6 / 50 (12.00%)
         occurrences all number
    15
    6
    Pyrexia
         subjects affected / exposed
    3 / 65 (4.62%)
    4 / 50 (8.00%)
         occurrences all number
    4
    5
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    13 / 65 (20.00%)
    12 / 50 (24.00%)
         occurrences all number
    13
    12
    Diarrhoea
         subjects affected / exposed
    13 / 65 (20.00%)
    3 / 50 (6.00%)
         occurrences all number
    18
    3
    Dysphagia
         subjects affected / exposed
    4 / 65 (6.15%)
    2 / 50 (4.00%)
         occurrences all number
    4
    2
    Dyspepsia
         subjects affected / exposed
    5 / 65 (7.69%)
    2 / 50 (4.00%)
         occurrences all number
    5
    2
    Stomatitis
         subjects affected / exposed
    13 / 65 (20.00%)
    11 / 50 (22.00%)
         occurrences all number
    14
    11
    Nausea
         subjects affected / exposed
    25 / 65 (38.46%)
    21 / 50 (42.00%)
         occurrences all number
    28
    25
    Vomiting
         subjects affected / exposed
    8 / 65 (12.31%)
    5 / 50 (10.00%)
         occurrences all number
    12
    6
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 65 (1.54%)
    3 / 50 (6.00%)
         occurrences all number
    1
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 65 (1.54%)
    3 / 50 (6.00%)
         occurrences all number
    1
    3
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 50 (0.00%)
         occurrences all number
    4
    0
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    6 / 65 (9.23%)
    2 / 50 (4.00%)
         occurrences all number
    7
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 65 (9.23%)
    5 / 50 (10.00%)
         occurrences all number
    8
    5
    Dehydration
         subjects affected / exposed
    2 / 65 (3.08%)
    3 / 50 (6.00%)
         occurrences all number
    2
    3
    Hyperglycaemia
         subjects affected / exposed
    3 / 65 (4.62%)
    4 / 50 (8.00%)
         occurrences all number
    3
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Apr 2021
    Amendment 1: The primary rationale for the amendment was to account for a study design update from a Phase III study to an adaptive Phase II/III study which allows for a proper balance of the risk and benefit of a Phase III expansion decision. Additional updates included were: eligibility criteria to address high risk of bleeds that are a feature inherent to the underlying disease of a population with HNSCC and define unstable medical condition; definition of second course of study treatment that was expanded to include participants who complete 35 cycles of study treatment.
    30 Jun 2021
    Amendment 2: A DIL dated 13-April-2021 was issued requiring the stopping of further screening and the discontinuation of the administration of GSK3359609 (feladilimab) or placebo for all participants on INDUCE-4, effective immediately. Further to the DIL, since all participants had the option to remain on pembrolizumab alone plus 5FU-platinum as study therapy, GSK issued a Protocol Clarification Letter (PCL) dated 28-April-2021 to reduce any unnecessary burden of on treatment and follow up assessments (the PCL did not alter any screening assessments). This protocol amendment was a follow up to the PCL, with a primary intent to only update the SoA; other impacted, relevant sections were also updated accordingly. Additionally, updates were made to management guidelines to align with pembrolizumab IB update.

    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.
    Data are reported following the interim analysis decision to stop further accrual into the study and discontinue feladilimab/placebo. The study primary completion analysis results should be interpreted with consideration of the immature data
    For support, Contact us.
    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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