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    Clinical Trial Results:
    A phase II, multicenter, randomized, two-arm study of capmatinib (INC280, an oral MET inhibitor) and spartalizumab (PDR001, a PD-1 inhibitor) combination therapy versus docetaxel in pretreated adult patients with EGFR wild-type, ALK rearrangement negative locally advanced/metastatic non-small cell lung cancer.

    Summary
    EudraCT number
    		 2018-001420-19
    Trial protocol
    		 DE   ES   GB   BE   FR   GR   BG   NL   IT   RO  
    Global end of trial date
    07 Sep 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    28 Aug 2021
    First version publication date
    24 Jun 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CINC280D2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03647488
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.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
    07 Sep 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial is to evaluate the safety and efficacy of capmatinib in combination with spartalizumab in adult participants with epidermal growth factor receptor (EGFR) wild type (for exon 19 deletions and exon 21 L858R substitution mutations), anaplastic lymphoma kinase (ALK) rearrangement negative in locally advanced (stage IIIB, not eligible for definitive chemo-radiation) or metastatic (stage IV) Non-small cell lung cancer (NSCLC) after failure of platinum doublet and checkpoint inhibitor treatment.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 In general, the use of any concomitant medication/therapy deemed necessary for the care of the participant (e.g. such as anti-emetics, anti-diarrhea) was permitted, except when specifically prohibited (e.g. such as CYP450 inducers, inhibitors, and substrates, gastric protecting agents, and other investigational and antineoplastic therapies).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Dec 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    18
    EEA total number of subjects
    15
    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)
    13
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Based on preliminary results of run-in part, the decision was not to open randomized part of the study. Therefore, no participants were enrolled in randomized part.

    Period 1
    Period 1 title
    Run-in part (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Run-in part: capmatinib + spartalizumab
    Arm description
    		 Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab 400 mg via intravenous infusion once every 28 days

    Investigational medicinal product name
    Capmatinib
    Investigational medicinal product code
    INC280
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capmatinib 400 mg (tablets) orally taken twice daily. The orally administered film-coated tablet formulation was provided in up to two strengths of 150 mg and 200 mg free base equivalent.

    Number of subjects in period 1
    		Run-in part: capmatinib + spartalizumab
    Started
    18
    Completed
    0
    Not completed
    18
         Clinical progression
    2
         Adverse event, non-fatal
    5
         Progressive disease
    10
         Refusal to take investigational product
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Run-in part: capmatinib + spartalizumab
    Reporting group description
    		 Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days

    Reporting group values
    		 Run-in part: capmatinib + spartalizumab Total
    Number of subjects
    		 18 18
    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)
    		 13 13
        From 65-84 years
    		 5 5
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.2 ( 10.52 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 7 7
        Male
    		 11 11
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 17 17
        Missing
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Run-in part: capmatinib + spartalizumab
    Reporting group description
    		 Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days

    Primary: Run-in part: Percentage of participants with Dose Limiting Toxicities (DLTs)

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    End point title
    		 Run-in part: Percentage of participants with Dose Limiting Toxicities (DLTs) [1]
    End point description
    A DLT was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.
    End point type
    Primary
    End point timeframe
    From the day of the first dose of study medication up to 56 days
    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: No statistical analyses were planned for this endpoint
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    18
    Units: Participants
        number (not applicable)
    5.56
    No statistical analyses for this end point

    Primary: Run-in part: Percentage of participants with adverse events (AEs)

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    End point title
    		 Run-in part: Percentage of participants with adverse events (AEs) [2]
    End point description
    Percentage of participants with AEs, including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0: Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: Death.
    End point type
    Primary
    End point timeframe
    From the day of the first dose of study medication to 150 days after the last dose of spartalizumab, or 30 days after the last dose of capmatinib (whichever is later) up to maximum duration of approximately 1.7 years
    Notes
    [2] - 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: No statistical analyses were planned for this endpoint
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    18
    Units: Percentage of Participants
    number (not applicable)
        AEs- All grades
    100
        AEs- Grade ≥3
    61.11
        Treatment-related (TR) AEs- All grades
    77.78
        TR AEs- Grade ≥3
    5.56
        Serious AEs (SAEs)- All grades
    55.56
        SAEs- Grade ≥3
    38.89
        TR SAEs- All grades
    16.67
        TR SAEs- Grade ≥3
    0
        Fatal SAEs- All grades
    5.56
        Fatal SAEs- Grade ≥3
    5.56
        AEs leading to discontinuation- All grades
    27.78
        AEs leading to discontinuation- Grade ≥3
    16.67
        TR AEs leading to discontinuation- All grades
    16.67
        TR AEs leading to discontinuation- Grade ≥3
    5.56
        AEs leading to adjustment/interruption-All grades
    50
        AEs leading to adjustment/interruption-Grade≥3
    27.78
        AEs requiring additional therapy- All grades
    88.89
        AEs requiring additional therapy- Grade ≥3
    44.44
    No statistical analyses for this end point

    Primary: Run-in part: Percentage of participants with at least one dose reduction.

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    End point title
    		 Run-in part: Percentage of participants with at least one dose reduction. [3]
    End point description
    Percentage of participants with at least one dose reduction. Dose reductions were only allowed for capmatinib
    End point type
    Primary
    End point timeframe
    From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks
    Notes
    [3] - 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: No statistical analyses were planned for this endpoint
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    18
    Units: Percentage of Participants
        number (not applicable)
    33.33
    No statistical analyses for this end point

    Primary: Run-in part: Percentage of participants with at least one dose interruption

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    End point title
    		 Run-in part: Percentage of participants with at least one dose interruption [4]
    End point description
    Percentage of participants with at least one dose interruption. Dose interruptions were allowed for capmatinib and spartalizumab.
    End point type
    Primary
    End point timeframe
    From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks
    Notes
    [4] - 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: No statistical analyses were planned for this endpoint
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    18
    Units: Percentage of Participants
    number (not applicable)
        Capmatinib
    44.44
        Spartalizumab
    16.67
    No statistical analyses for this end point

    Primary: Run-in part: Relative dose intensity received by participants

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    End point title
    		 Run-in part: Relative dose intensity received by participants [5]
    End point description
    The relative dose intensity of capmatinib and spartalizumab is computed as the ratio of dose intensity and planned dose intensity, expressed as a percentage.
    End point type
    Primary
    End point timeframe
    From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks
    Notes
    [5] - 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: No statistical analyses were planned for this endpoint
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    18
    Units: Percentage of dose received
    median (full range (min-max))
        Capmatinib
    99.6 (27.8 to 100.0)
        Spartalizumab
    100.0 (75.0 to 133.3)
    No statistical analyses for this end point

    Secondary: Objective response rate (ORR) based on RECIST 1.1 and as per investigator assessment

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    End point title
    		 Objective response rate (ORR) based on RECIST 1.1 and as per investigator assessment
    End point description
    ORR is defined as the proportion of subjects with best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and as per investigator assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. ORR results for randomized part are not available because randomized part never started.
    End point type
    Secondary
    End point timeframe
    From start of treatment until end of treatment, assessed up to 68 weeks (run-in part)
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    18
    Units: Percentage of participants
        number (confidence interval 95%)
    0 (0.0 to 18.5)
    No statistical analyses for this end point

    Secondary: Disease control rate (DCR) based on RECIST 1.1 and as per investigator assessment

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    End point title
    		 Disease control rate (DCR) based on RECIST 1.1 and as per investigator assessment
    End point description
    DCR is defined as the proportion of subjects with best overall response of CR or PR or stable disease based on RECIST 1.1 and as per investigator assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Stable disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression. DCR results for randomized part are not available because randomized part never started.
    End point type
    Secondary
    End point timeframe
    From start of treatment until end of treatment, assessed up to 68 weeks (run-in part)
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    18
    Units: Percentage of participants
        number (confidence interval 95%)
    27.8 (9.7 to 53.5)
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    PFS is defined as the time from the date of start of treatment to the date of the first documented radiological progression or death due to any cause. For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. Progression is defined using RECIST 1.1 and as per investigator assessment as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS results for randomized part are not available because randomized part never started.
    End point type
    Secondary
    End point timeframe
    From start of treatment until the first documented radiological progression or death, whichever comes first, assessed up to 68 weeks (run-in part)
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    18
    Units: Months
        median (confidence interval 95%)
    1.9 (1.7 to 3.6)
    No statistical analyses for this end point

    Secondary: Time to response (TTR) based on RECIST 1.1 and as per investigator assessment

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    End point title
    		 Time to response (TTR) based on RECIST 1.1 and as per investigator assessment
    End point description
    TTR is defined as the time from the date of start of treatment to the first documented response of either CR or PR, which must be subsequently confirmed. TTR was evaluated according to RECIST 1.1 and as per investigator assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. For run-in part, TTR results are not available because there were no participants achieving response (CR or PR) For randomized part , TTR results are not available because randomized part never started.
    End point type
    Secondary
    End point timeframe
    From start of treatment to the first documented response of either complete response or partial response, assessed up to 68 weeks (run-in part)
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    0 [6]
    Units: Months
        number (confidence interval 95%)
    ( to )
    Notes
    [6] - No data available as no participants had event
    No statistical analyses for this end point

    Secondary: AUClast of capmatinib

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    End point title
    		 AUClast of capmatinib
    End point description
    AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods.
    End point type
    Secondary
    End point timeframe
    Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    8
    Units: nanogram*hour/milliliter (ng*hr/mL)
        geometric mean (geometric coefficient of variation)
    11500 ( 47.3 )
    No statistical analyses for this end point

    Secondary: Duration of response (DOR) based on RECIST 1.1 and as per investigator assessment

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    End point title
    		 Duration of response (DOR) based on RECIST 1.1 and as per investigator assessment
    End point description
    DOR is the time between the date of first documented response(CR or PR) and the date of first documented progression or death due to underlying cancer based on RECIST1.1 and as per investigator assessment. If progression or death has not occurred, the subject is censored at the date of last adequate tumor assessment. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Progression: at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. The sum must also demonstrate an absolute increase of at least 5 mm. Results are not available because there were no participants achieving response in the run-in part and randomized part never started
    End point type
    Secondary
    End point timeframe
    From first documented response (CR or PR) to first documented progression or death, whichever came first, assessed up to 68 weeks (run-in part)
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    0 [7]
    Units: Months
        median (confidence interval 95%)
    ( to )
    Notes
    [7] - No data available as no participants had event
    No statistical analyses for this end point

    Secondary: AUCtau of capmatinib

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    End point title
    		 AUCtau of capmatinib
    End point description
    AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods.
    End point type
    Secondary
    End point timeframe
    Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    5
    Units: nanogram*hour/milliliter (ng*hr/mL)
        geometric mean (geometric coefficient of variation)
    12800 ( 48.5 )
    No statistical analyses for this end point

    Secondary: Maximum plasma concentration (Cmax) of capmatinib

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    End point title
    		 Maximum plasma concentration (Cmax) of capmatinib
    End point description
    The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods.
    End point type
    Secondary
    End point timeframe
    Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    8
    Units: nanogram/milliliter (ng/mL)
        geometric mean (geometric coefficient of variation)
    3260 ( 44.6 )
    No statistical analyses for this end point

    Secondary: Time to reach maximum (Tmax) plasma concentration of capmatinib

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    End point title
    		 Time to reach maximum (Tmax) plasma concentration of capmatinib
    End point description
    Tmax is the time to reach maximum (peak) plasma concentration of capmatinib after single dose administration (time). Tmax was calculated using non-compartmental methods.
    End point type
    Secondary
    End point timeframe
    Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    8
    Units: hour (h)
        median (full range (min-max))
    1.42 (0.983 to 2.00)
    No statistical analyses for this end point

    Secondary: AUClast of spartlizumab

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    End point title
    		 AUClast of spartlizumab
    End point description
    AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods.
    End point type
    Secondary
    End point timeframe
    Cycle 3 day 1 (at predose and 1 hour postdose), cycle 3 day 4, cycle 3 day 8, cycle 3 day 15. Each Cycle is 28 days
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    7
    Units: microgram*day/milliliter (μg*day/mL)
        geometric mean (geometric coefficient of variation)
    1720 ( 64.5 )
    No statistical analyses for this end point

    Secondary: AUCtau of spartlizumab

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    End point title
    		 AUCtau of spartlizumab
    End point description
    AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods.
    End point type
    Secondary
    End point timeframe
    Cycle 3 day 1 (at predose and 1 hour postdose), cycle 3 day 4, cycle 3 day 8, cycle 3 day 15. Each Cycle is 28 days
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    7
    Units: microgram*day/milliliter (μg*day/mL)
        geometric mean (geometric coefficient of variation)
    2110 ( 35.1 )
    No statistical analyses for this end point

    Secondary: Maximum plasma concentration (Cmax) of spartlizumab

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    End point title
    		 Maximum plasma concentration (Cmax) of spartlizumab
    End point description
    The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods.
    End point type
    Secondary
    End point timeframe
    Cycle 3 day 1 (at predose and 1 hour postdose), cycle 3 day 4, cycle 3 day 8, cycle 3 day 15. Each Cycle is 28 days
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    8
    Units: microgram/milliliter (μg/mL)
        geometric mean (geometric coefficient of variation)
    138 ( 23.2 )
    No statistical analyses for this end point

    Secondary: Time to reach maximum (Tmax) plasma concentration of spartlizumab

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    End point title
    		 Time to reach maximum (Tmax) plasma concentration of spartlizumab
    End point description
    Tmax is the time to reach maximum (peak) plasma concentration of spartlizumab after single dose administration (time). Tmax was calculated using non-compartmental methods.
    End point type
    Secondary
    End point timeframe
    Cycle 3 day 1 (at predose and 1 hour postdose), cycle 3 day 4, cycle 3 day 8, cycle 3 day 15. Each Cycle is 28 days
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    8
    Units: hour (h)
        median (full range (min-max))
    1.13 (1.00 to 1.53)
    No statistical analyses for this end point

    Secondary: Spartalizumab antidrug antibodies (ADA) prevalence at baseline

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    End point title
    		 Spartalizumab antidrug antibodies (ADA) prevalence at baseline
    End point description
    ADA prevalence at baseline was calculated as the proportion of participants who had an ADA positive result at baseline
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 at predose. Each Cycle is 28 days
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    17
    Units: Participants
    3
    No statistical analyses for this end point

    Secondary: Spartalizumab ADA Incidence On-treatment

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    End point title
    		 Spartalizumab ADA Incidence On-treatment
    End point description
    ADA incidence on treatment was calculated as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)
    End point type
    Secondary
    End point timeframe
    Predose at Cycle (C)1 Day (D)1, C2D1, C3D1, C4D1, C6D1, C8D1, C10D1, C12D1, thereafter every 6 cycles until discontinuation, and end of treatment (EOT), 30-day and 150-day after EOT
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    14
    Units: Participants
    3
    No statistical analyses for this end point

    Post-hoc: All Collected Deaths

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    End point title
    		 All Collected Deaths
    End point description
    On-treatment deaths due to any cause were collected from first dose of study medication to 150 days after the last dose of spartalizumab, or 30 days after the last dose of capmatinib, whichever is later, up to a maximum duration of approximately 1.7 years. Total deaths were collected from first dose of study treatment until end of post-treatment efficacy or survival follow, up to maximum duration of approximately 1.7 years
    End point type
    Post-hoc
    End point timeframe
    On-treatment: up to approximately 1.7 years. All deaths: up to approximately 1.7 years
    End point values
    		 Run-in part: capmatinib + spartalizumab
    Number of subjects analysed
    18
    Units: Participants
        Total Deaths
    12
        Deaths on-treatment
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment adverse events and deaths due to any cause were collected from first dose of study medication to 150 days after the last dose of spartalizumab, or 30 days after the last dose of capmatinib, whichever is later, up to approx. 1.7 years.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Run-in part: capmatinib + spartalizumab
    Reporting group description
    		 Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days

    Serious adverse events
    		 Run-in part: capmatinib + spartalizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 18 (55.56%)
         number of deaths (all causes)
    5
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Run-in part: capmatinib + spartalizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 18 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    4
    Axillary pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    4
    Chest pain
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Oedema peripheral
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    4
    Pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    5
    Reproductive system and breast disorders
    Nipple pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Bronchospasm
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Dysphonia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    5 / 18 (27.78%)
         occurrences all number
    5
    Dyspnoea exertional
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pleural effusion
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Productive cough
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Depression
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Confusional state
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Sleep disorder
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Amylase increased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Blood creatinine increased
         subjects affected / exposed
    5 / 18 (27.78%)
         occurrences all number
    6
    Blood magnesium decreased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    C-reactive protein increased
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Creatinine renal clearance decreased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Lipase increased
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Weight decreased
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Dysgeusia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Somnolence
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Lethargy
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Gastrointestinal disorders
    Cheilitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Abdominal pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    5 / 18 (27.78%)
         occurrences all number
    6
    Dry mouth
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Dysphagia
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    7 / 18 (38.89%)
         occurrences all number
    7
    Stomatitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    5 / 18 (27.78%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Rash macular
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Renal and urinary disorders
    Renal pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Osteomyelitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pneumonia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    3
    Decreased appetite
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Hyperglycaemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1

    More information

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

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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