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    Clinical Trial Results:
    A Randomized, Phase 3, Open-Label Study of Combinations of REGN2810 (Cemiplimab, Anti-PD-1 Antibody), Platinum based Doublet Chemotherapy, and Ipilimumab (Anti-CTLA-4 Antibody) Versus Pembrolizumab Monotherapy in First-Line Treatment of Patients With Advanced or Metastatic Non-Small Cell Lung Cancer With Tumors Expressing PD-L1 ≥50%

    Summary
    EudraCT number
    2017-001041-27
    Trial protocol
    NL   LT   GB   AT   IT  
    Global end of trial date
    29 Jul 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Aug 2022
    First version publication date
    12 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    R2810-ONC-16111
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03515629
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Road, Tarrytown, NY, United States, 10591
    Public contact
    Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., 001 844-734-6643, clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., 001 844-734-6643, clinicaltrials@regeneron.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
    02 Aug 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to compare the progression-free survival (PFS) of cemiplimab plus ipilimumab combination therapy (hereinafter referred to as cemiplimab/ipi) and cemiplimab plus 2 cycles only of platinum-based doublet chemotherapy plus ipilimumab combination therapy (hereinafter referred to as “cemiplimab/chemo/ipi”) with standard-of-care pembrolizumab monotherapy in the first line treatment of patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC) whose tumors express programmed death ligand 1 (PD L1) in ≥50% of tumor cells.
    Protection of trial subjects
    It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Jul 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    5
    EEA total number of subjects
    2
    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)
    4
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 3 centers that randomized 5 participants in the United States, Lithuania, and Italy.

    Pre-assignment
    Screening details
    Due to program de-prioritization, the sponsor decided to cease enrollment at which time only 5 participants were randomized to 2 of 3 treatment arms (i.e. no participants were randomized to receive pembrolizumab).

    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
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W
    Arm description
    Cemiplimab was administered at 350 mg as an intravenous (IV) infusion every 3 weeks (Q3W) for 108 weeks in combination with ipilimumab administered IV over approximately 90 minutes at 50 mg Q6W for up to 4 doses.
    Arm type
    Experimental

    Investigational medicinal product name
    ipilimumab
    Investigational medicinal product code
    Other name
    Yervoy
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV ipilimumab 50 mg Q6W

    Investigational medicinal product name
    cemiplimab
    Investigational medicinal product code
    REGN2810
    Other name
    Libtayo
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV cemiplimab 350 mg Q3W

    Arm title
    Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Arm description
    Cemiplimab was administered at 350 mg as an IV infusion Q3W for 108 weeks in combination with platinum-based doublet chemotherapy administered IV Q3W for 2 cycles and with ipilimumab administered IV over approximately 90 minutes at 50 mg Q6W for up to 4 doses.
    Arm type
    Experimental

    Investigational medicinal product name
    carboplatin
    Investigational medicinal product code
    Other name
    Platinum-based doublet chemotherapy
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV carboplatin 10 mg/mL

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Platinum-based doublet chemotherapy
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV paclitaxel

    Investigational medicinal product name
    pemetrexed
    Investigational medicinal product code
    Other name
    Platinum-based doublet chemotherapy
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV pemetrexed 1 mg/mL

    Investigational medicinal product name
    cisplatin
    Investigational medicinal product code
    Other name
    Platinum-based doublet chemotherapy
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV cisplatin 1 mg/mL

    Number of subjects in period 1
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Started
    3
    2
    Completed
    1
    1
    Not completed
    2
    1
         Progressive disease
    1
    -
         Adverse event, serious fatal
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W
    Reporting group description
    Cemiplimab was administered at 350 mg as an intravenous (IV) infusion every 3 weeks (Q3W) for 108 weeks in combination with ipilimumab administered IV over approximately 90 minutes at 50 mg Q6W for up to 4 doses.

    Reporting group title
    Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Reporting group description
    Cemiplimab was administered at 350 mg as an IV infusion Q3W for 108 weeks in combination with platinum-based doublet chemotherapy administered IV Q3W for 2 cycles and with ipilimumab administered IV over approximately 90 minutes at 50 mg Q6W for up to 4 doses.

    Reporting group values
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W Total
    Number of subjects
    3 2 5
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    2 2 4
        From 65-84 years
    1 0 1
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    61.7 ± 9.29 56.5 ± 4.95 -
    Sex: Female, Male
    Units: Participants
        Female
    3 0 3
        Male
    0 2 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    0 0 0
        White
    3 2 5
        More than one race
    0 0 0
        Unknown or Not Reported
    0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 0 0
        Not Hispanic or Latino
    3 2 5
        Unknown or Not Reported
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W
    Reporting group description
    Cemiplimab was administered at 350 mg as an intravenous (IV) infusion every 3 weeks (Q3W) for 108 weeks in combination with ipilimumab administered IV over approximately 90 minutes at 50 mg Q6W for up to 4 doses.

    Reporting group title
    Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Reporting group description
    Cemiplimab was administered at 350 mg as an IV infusion Q3W for 108 weeks in combination with platinum-based doublet chemotherapy administered IV Q3W for 2 cycles and with ipilimumab administered IV over approximately 90 minutes at 50 mg Q6W for up to 4 doses.

    Primary: Progression-Free Survival (PFS) as assessed by a blinded Independent Review Committee (IRC) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) assessments

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    End point title
    Progression-Free Survival (PFS) as assessed by a blinded Independent Review Committee (IRC) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) assessments [1]
    End point description
    Per protocol, the final analysis of PFS was to be performed after observing 142 PFS events in the pembrolizumab treatment arm. PFS was not assessed due to insufficient data collected.
    End point type
    Primary
    End point timeframe
    Up to 32 months
    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: Due to ceasing enrollment early, no participants were randomized to receive pembrolizumab.
    End point values
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [2] - PFS was not assessed due to insufficient data collected.
    [3] - PFS was not assessed due to insufficient data collected.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Per protocol, if the final analysis of PFS was statistically significant for both cemiplimab combination therapy versus pembrolizumab treatment, the analysis of OS for cemiplimab combinations-versus-pembrolizumab comparison was to be performed at the time of PFS analysis, 12 months, and 18 months after analysis of PFS using the same method as used in the analysis of PFS; however, OS was not assessed due to insufficient data collected.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [4] - OS was not assessed due to insufficient data collected.
    [5] - OS was not assessed due to insufficient data collected.
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR)
    End point description
    Per protocol, the ORR for each cemiplimab combination-versus-pembrolizumab comparison was to be analyzed using the Cochran-Mantel-Haenszel test stratified by histological status (non-squamous versus squamous).
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: Not Applicable
        number (not applicable)
    Notes
    [6] - OS was not assessed due to insufficient data collected.
    [7] - OS was not assessed due to insufficient data collected.
    No statistical analyses for this end point

    Secondary: Number of Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Number of Treatment-Emergent Adverse Events (TEAEs)
    End point description
    Safety analysis set (SAF), defined as all enrolled participants who received any amount of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Number of subjects analysed
    3
    2
    Units: Events
    68
    91
    No statistical analyses for this end point

    Secondary: Number of Participants with Dose-Limiting Toxicities (DLTs)

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    End point title
    Number of Participants with Dose-Limiting Toxicities (DLTs)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Number of subjects analysed
    3
    2
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Any Serious TEAEs

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    End point title
    Number of Participants with Any Serious TEAEs
    End point description
    Safety analysis set (SAF), defined as all enrolled participants who received any amount of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Number of subjects analysed
    3
    2
    Units: Participants
    2
    2
    No statistical analyses for this end point

    Secondary: Number of Deaths

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    End point title
    Number of Deaths
    End point description
    Safety analysis set (SAF), defined as all enrolled participants who received any amount of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Number of subjects analysed
    3
    2
    Units: Participants
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Laboratory Abnormalities

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    End point title
    Number of Participants with Laboratory Abnormalities
    End point description
    Safety analysis set (SAF), defined as all enrolled participants who received any amount of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Number of subjects analysed
    3
    2
    Units: Participants
    1
    1
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) at 12 months

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    End point title
    Overall Survival (OS) at 12 months
    End point description
    Per protocol, if the final analysis of PFS was statistically significant for both cemiplimab combination therapy versus pembrolizumab treatment, the analysis of OS for cemiplimab combinations-versus-pembrolizumab comparison was to be performed at the time of PFS analysis, 12 months, and 18 months after analysis of PFS using the same method as used in the analysis of PFS.
    End point type
    Secondary
    End point timeframe
    At 12 months
    End point values
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: Not Applicable
        number (not applicable)
    Notes
    [8] - OS was not assessed due to insufficient data collected.
    [9] - OS was not assessed due to insufficient data collected.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) at 18 months

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    End point title
    Overall Survival (OS) at 18 months
    End point description
    Per protocol, if the final analysis of PFS was statistically significant for both cemiplimab combination therapy versus pembrolizumab treatment, the analysis of OS for cemiplimab combinations-versus-pembrolizumab comparison was to be performed at the time of PFS analysis, 12 months, and 18 months after analysis of PFS using the same method as used in the analysis of PFS.
    End point type
    Secondary
    End point timeframe
    At 18 months
    End point values
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: Not Applicable
        number (not applicable)
    Notes
    [10] - OS was not assessed due to insufficient data collected.
    [11] - OS was not assessed due to insufficient data collected.
    No statistical analyses for this end point

    Secondary: Quality of Life (Core 30 Questionnaire)

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    End point title
    Quality of Life (Core 30 Questionnaire)
    End point description
    Quality of Life (QoL) as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) four-point scale, with 1 as "not at all" and 4 as "very much." Per protocol, the change in EORTC QLQ-C30 scores from the first assessment to the end of the study were to be summarized descriptively at each post-baseline time point and compared using a mixed effects model, if appropriate.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: Not Applicable
        number (not applicable)
    Notes
    [12] - The EORTC QLQ-C30 was not assessed due to insufficient data collected.
    [13] - The EORTC QLQ-C30 was not assessed due to insufficient data collected.
    No statistical analyses for this end point

    Secondary: Quality of Life (Lung Cancer 13 Questionnaire)

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    End point title
    Quality of Life (Lung Cancer 13 Questionnaire)
    End point description
    QoL as measured by the Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) to assess lung cancer-associated symptoms and treatment-related side effects among lung cancer patients. The scale for EORTC-QLQ-LC13 is 1-4 for most outcome measures of systems, with 1 rated as “not at all” and 4 rated as “very much." Per protocol, the change in EORTC QLQ-LC13 scores from the first assessment to the end of the study were to be summarized descriptively at each post-baseline time point and compared using a mixed effects model, if appropriate.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + chemotherapy + ipilimumab 50 mg Q6W
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: Not Applicable
        number (not applicable)
    Notes
    [14] - The EORTC QLQ-LC13 was not assessed due to insufficient data collected.
    [15] - The EORTC QLQ-LC13 was not assessed due to insufficient data collected.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug to end of study (up to 32 months)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Cemiplimab 350 mg Q3W + chemotherapy+ ipilimumab 50 mg Q6W
    Reporting group description
    -

    Reporting group title
    Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W
    Reporting group description
    -

    Serious adverse events
    Cemiplimab 350 mg Q3W + chemotherapy+ ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    2 / 3 (66.67%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrointestinal disorders
    Enterocolitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cemiplimab 350 mg Q3W + chemotherapy+ ipilimumab 50 mg Q6W Cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    3 / 3 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Hypotension
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Aortic arteriosclerosis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pseudoprogression
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    Fatigue
         subjects affected / exposed
    2 / 2 (100.00%)
    2 / 3 (66.67%)
         occurrences all number
    2
    4
    Pain
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Asthenia
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    3
    Influenza like illness
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Suprapubic pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    3
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Thermal burn
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Liver function test increased
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Palpitations
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Dyspnoea
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Haemoptysis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Pneumonitis
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    2
    Pulmonary oedema
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Neutropenia
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Leukopenia
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 2 (100.00%)
    1 / 3 (33.33%)
         occurrences all number
    3
    1
    Headache
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    3
    4
    Balance disorder
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Paraesthesia
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 2 (100.00%)
    1 / 3 (33.33%)
         occurrences all number
    4
    1
    Abdominal pain
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    2 / 2 (100.00%)
    1 / 3 (33.33%)
         occurrences all number
    7
    2
    Constipation
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Dyspepsia
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Vomiting
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    3
    Gastritis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Oliguria
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Alopecia
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Rash
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    Pruritus
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Hair colour changes
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Skin reaction
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    Arthralgia
         subjects affected / exposed
    1 / 2 (50.00%)
    2 / 3 (66.67%)
         occurrences all number
    1
    2
    Back pain
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Muscle spasms
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Adrenocortical insufficiency acute
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Hyperthyroidism
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 2 (100.00%)
    1 / 3 (33.33%)
         occurrences all number
    5
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 2 (100.00%)
    1 / 3 (33.33%)
         occurrences all number
    3
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Hypochloraemia
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    Metabolic acidosis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Infections and infestations
    Fungal oesophagitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    2
    Otitis media acute
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Nov 2017
    The redesigned study is a phase 3, randomized, global, open-label, pivotal, study of the efficacy and safety of REGN2810/ipilimumab versus REGN2810/chemotherapy/ipilimumab versus pembrolizumab monotherapy in patients with stage IIIB or stage IV squamous or non squamous NSCLC whose tumors express PD L1 in ≥50% of tumor cells and who have received no prior systemic treatment for their advanced disease. In the redesigned study, the study arms A and C remain the same; arm B will evaluate REGN2810 in combination with ipilimumab instead of chemotherapy. Rationale revised to reflect the new study design. Due to a new statistical design, enrollment of approximately 585 subjects is needed to generate enough progression free survival (PFS) events. Therefore, the approximate number of planned subjects is reduced to 585 from 675. An interim analysis for secondary endpoint of OS will be performed at the time of primary analysis for PFS
    23 Feb 2018
    The current text of Key Secondary Endpoint “A patient who has not died will be censored at the last known date of contact" has been revised to "A patient who is lost to follow-up will be censored at the last date that the patient was known to be alive", following European Union (EU) regulatory review; Revised the exclusion criteria concerning human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) to clarify that patients with uncontrolled infection are excluded, but patients with controlled infection are permitted, as requested following EU regulatory review; The current text: “REGN2810 C2P1 drug product is supplied as a sterile liquid solution of 5.6 or 7.4 mL in a 10 or 20 mL glass vial for IV administration.” is revised to “REGN2810 C2P1 drug product is supplied as a sterile liquid solution of 5.6 mL in a 10 mL glass vial for IV administration.” as requested following EU regulatory review.
    16 Mar 2018
    The following text added to exclusion criterion #10 “patients with HIV or hepatitis must have their disease reviewed by the specialist (e.g., infectious disease or hepatologist) managing this disease prior to commencing and throughout the duration of their participation in the trial” following European Union (EU) regulatory review.
    14 May 2018
    Clarified: Patients on treatment Arm C, pemetrexed maintenance is not allowed; Clarified: Patients in follow-up may be offered retreatment up to an additional 108 wks; Revised secondary endpoint text: To assess predictive utility of baseline PD L1 tumor expression levels on clinical response; Clarified list of Other Secondary Objectives; Inclusion criterion revised to add stage IIIC patient eligibility & clarified histologic diagnosis of NSCLC may be confirmed by central lab; Gemcitabine options for platinum-based doublet deleted; Chemotherapy cycles changed to 4 cycles; Text deleted regarding brain scans during treatment & follow-up periods; PK/ADA sample collection time points revised; Clarified: If possible, a tumor biopsy should be collected at time of progressive disease; Clarified exclusion criteria #3, #23; Exclusion criteria #24 & #25 added based on a health authority feedback; Clarified: Tumor tissue samples will also be tested for EGFR mutations & ALK translocations as well as for ROS1 fusions by a central lab, unless testing already performed & results available from other Regeneron NSCLC immunotherapy studies; Text deleted from Biomarker procedures; Text revised in screening visit assessments; Electrocardiogram text revised; Text added on request by regulatory authority: If necessary, samples may also be used for ADA assessments of ipilimumab; Text revised: Each vial will contain withdrawable cemiplimab at a concentration of 50 mg/mL; Clarified: Pre-medications are not required prior to first administration of cemiplimab & pre-treatment with vitamin supplementation is to start within 3 days of randomization for patients with non-squamous NSCLC; Text added: Pemetrexed maintenance therapy should be given according to local prescribing information & practice guidelines; Deleted “standard-of-care” in regard to platinum-based chemotherapy(ies); Changed REGN2810 to cemiplimab & other minor editorial changes made throughout protocol.

    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 the time of administrative close of study, a total of 5 patients were randomized to 2 treatment arms. With limited data, only important demographic and safety parameters were summarized.
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