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    Clinical Trial Results:
    A multicenter phase II study evaluating denosumab (XGEVA®) in combination with nivolumab (OPDIVO®) as second-line therapy for patients with stage IV non-small–cell lung cancer (squamous and non-squamous) with bone metastases

    Summary
    EudraCT number
    		 2018-001105-85
    Trial protocol
    		 FR  
    Global end of trial date
    19 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Mar 2025
    First version publication date
    20 Mar 2025
    Other versions
    Summary report(s)
    		 DENIVOS CSR Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    P_2017_007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03669523
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Centre Hospitalier Annecy Genevois
    Sponsor organisation address
    1 avenue de l'Hopital, EPAGNY METZ TESSY, France, 74370
    Public contact
    Marion GHIDI, Centre Hospitalier Annecy Genevois, +33 (0)4 50 63 70 31, mghidi@ch-annecygenevois.fr
    Scientific contact
    Marion GHIDI, Centre Hospitalier Annecy Genevois, +33 (0)4 50 63 70 31, mghidi@ch-annecygenevois.fr
    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
    30 Sep 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Oct 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the Objective Response Rate (Complete Responses and Partial Responses) according to the PD-L1–expression rate (determined by immunohistochemistry and considered positive when ≥1% of the tumor cells are labeled) in Non-Small Cell Lung Cancer patients with bone metastases treated with the second-line denosumab–nivolumab combination.
    Protection of trial subjects
    The study was performed in accordance with the current version of the declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013). The trial was conducted in agreement with the International Conference on Harmonisation (ICH) guidelines on Good Clinical Practice (GCP). During the pre-inclusion visit, the investigator informed the patient and answered all questions concerning the objective, constraints, foreseeable risks and expected benefits of the trial. The investigator also specified the patient’s rights within the framework of biomedical research and verifies eligibility criteria. Copies of the information note and the consent form were given to the patient by the investigator. The patient information note detailed the procedures involved in the study (aims, methodology, potential risks, anticipated benefits) and the investigator explained these to each patient. After this information session, the patient had a minimum 2-day reflection period. During the inclusion visit, the patient’s inclusion and non-inclusion criteria were validated by the investigating physician and, if the patient gave his/her written consent, the investigator could proceed to include the patient. When the patient agreed to participate, the doctor and patient wrote their names and surnames, dated and signed the consent form. The different copies of the information note and the consent form were distributed as follows: - Copies of the information note and signed consent form were given to the patient. - The original was saved by the investigator (even if the patient changes residence during the trial) in a safe place not accessible to third parties, for a duration of 30 years after the end of the trial. All patients provided written informed consent to participate in the study prior to being screened.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Nov 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
    France: 82
    Worldwide total number of subjects
    82
    EEA total number of subjects
    82
    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)
    33
    From 65 to 84 years
    48
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 National, multicenter, prospective, open phase II trial, single arm, testing the Denosumab–Nivolumab combination as second-line therapy for patients with stage IV NSCLCs and bone metastases. It was planned to include a total of 86 patients during a 36 months inclusion period. Date of first enrolment: 2018/11/08 Date of last completed : 2023/10/19

    Pre-assignment
    Screening details
    		 Patients were recruited among those managed in consultations or hospitalization in 20-30 participating GFPC centers.

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

    Arms
    Arm title
    		 Denosumab + Nivolumab combination
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    DENOSUMAB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    120 mg every 4 weeks

    Investigational medicinal product name
    NIVOLUMAB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg, IV infusion over 30 minutes, every 2 weeks

    Number of subjects in period 1
    		Denosumab + Nivolumab combination
    Started
    82
    Completed
    82

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 82 82
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 33 33
        From 65-84 years
    		 48 48
        85 years and over
    		 1 1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 67 (61 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 17 17
        Male
    		 65 65
    PDL-1 status
    Units: Subjects
        PDL-1 negative
    		 39 39
        PDL-1 positive
    		 43 43
    Body Mass Index
    Units: kg/m²
        median (inter-quartile range (Q1-Q3))
    		 23.7 (21 to 25.8) -
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) was comprised of the 82 included patients who had at least one tumoral evaluation at inclusion, and as the trial is conducted in Intention-To-Treat (ITT).

    Subject analysis set title
    Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Four patients were excluded from Full analysis set because of major deviations, leaving 78 patients in the Per Protocol (PP) population.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population was comprised a total of 82 patients and correspond to ITT population

    Subject analysis sets values
    		 Full analysis set Per protocol set Safety analysis set
    Number of subjects
    82
    78
    82
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    33
    33
    33
        From 65-84 years
    48
    44
    48
        85 years and over
    1
    1
    1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    67 (61 to 73)
    66 (61 to 72)
    67 (61 to 73)
    Gender categorical
    Units: Subjects
        Female
    17
    16
    17
        Male
    65
    62
    65
    PDL-1 status
    Units: Subjects
        PDL-1 negative
    39
    36
    39
        PDL-1 positive
    43
    42
    43
    Body Mass Index
    Units: kg/m²
        median (inter-quartile range (Q1-Q3))
    23.7 (21 to 25.8)
    23.7 (21.2 to 25.8)
    23.7 (21 to 25.8)

    End points

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    End points reporting groups
    Reporting group title
    Denosumab + Nivolumab combination
    Reporting group description
    		 -

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) was comprised of the 82 included patients who had at least one tumoral evaluation at inclusion, and as the trial is conducted in Intention-To-Treat (ITT).

    Subject analysis set title
    Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Four patients were excluded from Full analysis set because of major deviations, leaving 78 patients in the Per Protocol (PP) population.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population was comprised a total of 82 patients and correspond to ITT population

    Primary: Overall Response Rate (ORR) by PD-L1 status

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    End point title
    		 Overall Response Rate (ORR) by PD-L1 status
    End point description
    End point type
    Primary
    End point timeframe
    Overall study duration
    End point values
    		 Denosumab + Nivolumab combination Full analysis set
    Number of subjects analysed
    82
    82
    Units: %
    number (confidence interval 95%)
        Overall
    12 (6.3 to 22)
    12 (6.3 to 22)
        PDL-1 negative
    8 (2 to 22)
    8 (2 to 22)
        PLD-1 positive
    16 (7.3 to 31)
    16 (7.3 to 31)
    Statistical analysis title
    		 Overall Response Rate by PDL-1 status
    Comparison groups
    Denosumab + Nivolumab combination v Full analysis set
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 2.14
    Notes
    [1] - Descriptive analysis

    Secondary: Overall Response Rate (ORR) by histological type

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    End point title
    		 Overall Response Rate (ORR) by histological type
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study duration
    End point values
    		 Denosumab + Nivolumab combination Full analysis set
    Number of subjects analysed
    82
    82
    Units: %
    number (confidence interval 95%)
        Overall
    12 (4.5 to 20)
    12 (4.5 to 20)
        Non-squamous
    10 (4.5 to 20)
    10 (4.5 to 20)
        Squamous
    23 (6.2 to 54)
    23 (6.2 to 54)
    No statistical analyses for this end point

    Secondary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study duration
    End point values
    		 Denosumab + Nivolumab combination Full analysis set Per protocol set
    Number of subjects analysed
    82
    82
    78
    Units: HR
    number (confidence interval 95%)
        Overall
    0.8 (0.54 to 1.19)
    0.8 (0.54 to 1.19)
    0.81 (0.54 to 1.22)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study duration
    End point values
    		 Denosumab + Nivolumab combination Full analysis set Per protocol set
    Number of subjects analysed
    82
    82
    78
    Units: HR
    number (confidence interval 95%)
        Overall
    0.78 (0.52 to 1.16)
    0.78 (0.52 to 1.16)
    0.79 (0.52 to 1.19)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Overall study duration
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Listing of adverse displayed by patient is available on demand.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2018
    - Modification of Inclusion/Non-inclusion Criteria - Protocol update based on Nivolumab and Denosumab PCRs - Grade correction for AST, ALT and total bilirubin for Nivolumab dose shifts or permanent discontinuation - Change in the calculation formula for creatinine clearance. - Correction of the interval between two cycles - Protocol updated to the latest NCI CTCAE version - Correction of the first meeting of the Independent Monitoring Committee
    05 Sep 2018
    Investigator list update
    16 May 2019
    - Modification of Inclusion/Non-inclusion criteria - Protocol update with definition of pseudoprogression - Addition of a bibliographic reference - Update Investigators List (V4.0)
    12 Sep 2019
    - Change of Project Manager and Statistician - Modification of Non-inclusion criteria - Investigators list update (V5.0)
    10 Feb 2020
    Investigator list update (V6.0)
    03 Aug 2020
    - Extension of recruitment period to 30/06/2021 - Modification of Inclusion/Non-Inclusion criteria
    12 May 2021
    - Extension of recruitment period to 31/12/2021

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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