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    Clinical Trial Results:
    A randomized, open label, multicenter phase II study evaluating the efficacy and safety of capmatinib (INC280) plus pembrolizumab versus pembrolizumab alone as first line treatment for locally advanced or metastatic non-small cell lung cancer with PD-L1≥ 50%

    Summary
    EudraCT number
    		 2019-002660-27
    Trial protocol
    		 GB   FR   BE   ES   GR   DE   NL   IT  
    Global end of trial date
    07 Feb 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Jan 2024
    First version publication date
    31 Jan 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CINC280I12201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04139317
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis, 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 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to evaluate the efficacy of capmatinib plus pembrolizumab in comparison to pembrolizumab alone.
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Jan 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    India: 7
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Japan: 2
    Country: Number of subjects enrolled
    Malaysia: 7
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    Thailand: 5
    Worldwide total number of subjects
    76
    EEA total number of subjects
    41
    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
    43
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 36 investigative sites in 16 countries.

    Pre-assignment
    Screening details
    		 The screening period began once patients had signed the study informed consent. Screening evaluations were performed within 28 days prior to the first dose of study treatment. After screening, the treatment period started on Cycle 1 Day 1.

    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
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W
    Arm description
    		 Capmatinib (INC280) 400 mg orally twice daily (BID) in combination with pembrolizumab 200 mg intravenously every 3 weeks (Q3W)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab (100 mg concentrate for solution for infusion or 50 mg lyophilized power for reconstitution for infusion) was administered intravenously at 200 mg once every 21 days.

    Investigational medicinal product name
    Capmatinib
    Investigational medicinal product code
    INC280
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capmatinib tablets were administered orally on a continuous twice daily (BID) dosing schedule at a dose level of 400 mg, from Day 1 until Day 21 of each 21-day cycle. Based on lack of tolerability observed in the capmatinib plus pembrolizumab arm, the study enrollment was halted per sponsor's decision. Immediately following the enrollment halt, capmatinib treatment was discontinued in subjects on the combination arm and all ongoing participants were allowed to continue receiving pembrolizumab single agent treatment.

    Arm title
    		 Pembrolizumab 200mg Q3W
    Arm description
    		 Pembrolizumab 200 mg intravenously every 3 weeks (Q3W)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab (100 mg concentrate for solution for infusion or 50 mg lyophilized power for reconstitution for infusion) was administered intravenously at 200 mg once every 21 days.

    Number of subjects in period 1
    		Capmatinib 400mg BID + pembrolizumab 200mg Q3W Pembrolizumab 200mg Q3W
    Started
    51
    25
    Entered post-treatment follow-up
    38
    20
    Completed
    10
    7
    Not completed
    41
    18
         Physician decision
    3
    1
         Subject Decision
    2
    2
         Adverse Event
    10
    2
         Death
    6
    4
         Progressive Disease
    19
    9
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Capmatinib 400mg BID + pembrolizumab 200mg Q3W
    Reporting group description
    		 Capmatinib (INC280) 400 mg orally twice daily (BID) in combination with pembrolizumab 200 mg intravenously every 3 weeks (Q3W)

    Reporting group title
    Pembrolizumab 200mg Q3W
    Reporting group description
    		 Pembrolizumab 200 mg intravenously every 3 weeks (Q3W)

    Reporting group values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W Pembrolizumab 200mg Q3W Total
    Number of subjects
    		 51 25 76
    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)
    		 23 10 33
        From 65-84 years
    		 28 15 43
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.7 ( 7.59 ) 66.6 ( 8.80 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 16 9 25
        Male
    		 35 16 51
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 25 16 41
        Asian
    		 22 8 30
        Unknown
    		 4 1 5

    End points

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    End points reporting groups
    Reporting group title
    Capmatinib 400mg BID + pembrolizumab 200mg Q3W
    Reporting group description
    		 Capmatinib (INC280) 400 mg orally twice daily (BID) in combination with pembrolizumab 200 mg intravenously every 3 weeks (Q3W)

    Reporting group title
    Pembrolizumab 200mg Q3W
    Reporting group description
    		 Pembrolizumab 200 mg intravenously every 3 weeks (Q3W)

    Primary: Progression-Free Survival (PFS) by investigator assessment as per RECIST 1.1

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    End point title
    		 Progression-Free Survival (PFS) by investigator assessment as per RECIST 1.1 [1]
    End point description
    PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. Tumor response was based on investigator assessment per RECISTv1.1. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment, the start of a subsequent anti-neoplastic therapy (if any) or the date of sponsor’s decision to discontinue capmatinib (applicable only to subjects on the combination arm). Due to the discontinuation of one of the investigational drugs (capmatinib) in all subjects in the combination arm, PFS was censored on 21-Jan-2021 or the last adequate tumor assessment prior to that date for the capmatinib plus pembrolizumab arm. PFS was analyzed using Kaplan-Meier estimates. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating not available). Therefore, NA values because of insufficient number of participants with events are indicated as 999
    End point type
    Primary
    End point timeframe
    Up to 1.3 years
    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 analysis were planned for this endpoint.
    End point values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W Pembrolizumab 200mg Q3W
    Number of subjects analysed
    51
    25
    Units: months
        median (confidence interval 95%)
    5.2 (2.0 to 999)
    5.1 (2.6 to 999)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) by investigator assessment as per RECIST 1.1

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    End point title
    		 Disease Control Rate (DCR) by investigator assessment as per RECIST 1.1
    End point description
    Tumor response was based on local investigator assessment per RECIST v1.1. DCR is defined as the percentage of participants with a BOR of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and non-CR/non-progressive disease (for subjects without target lesions). For the capmatinib plus pembrolizumab arm, 21-Jan-2021 or any last adequate tumor assessment prior to that date was considered as the end of evaluation period for BOR. For RECIST v1.1, 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; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression).
    End point type
    Secondary
    End point timeframe
    Up to 1.3 years
    End point values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W Pembrolizumab 200mg Q3W
    Number of subjects analysed
    51
    25
    Units: percentage of participants
        number (confidence interval 95%)
    37.3 (24.1 to 51.9)
    60.0 (38.7 to 78.9)
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) by investigator assessment as per RECIST 1.1

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    End point title
    		 Overall Response Rate (ORR) by investigator assessment as per RECIST 1.1
    End point description
    Tumor response was based on local investigator assessment as RECIST v1.1. ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response (BOR) of Complete Response (CR) or Partial Response (PR). For the capmatinib plus pembrolizumab arm, 21-Jan-2021 or any last adequate tumor assessment prior to that date was considered as the end of evaluation period for BOR. For RECIST v1.1, 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.
    End point type
    Secondary
    End point timeframe
    Up to 1.3 years
    End point values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W Pembrolizumab 200mg Q3W
    Number of subjects analysed
    51
    25
    Units: Percentage of participants
        number (confidence interval 95%)
    9.8 (3.3 to 21.4)
    40.0 (21.1 to 61.3)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS is defined as the time from the date of randomization to date of death due to any cause. The requirement for survival follow-up period was removed following the discontinuation of one of the investigational drugs (capmatinib) in all subjects in the combination arm and the implementation of Protocol Amendment 03. OS was analyzed using the Kaplan-Meier method as defined in the statistical analysis plan. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Up to 2.1 years
    End point values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W Pembrolizumab 200mg Q3W
    Number of subjects analysed
    51
    25
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) by investigator assessment as per RECIST 1.1

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    End point title
    		 Duration of Response (DOR) by investigator assessment as per RECIST 1.1
    End point description
    DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment of overall lesion response according to RECIST v1.1. DOR is defined as the time from the date of first documented response (confirmed CR or confirmed PR) to the date of first documented disease progression or death due to any cause. If a patient not had an event, duration was censored at the date of last adequate tumor assessment before the start of a new anticancer therapy, if any. DOR was analyzed using the Kaplan-Meier method as defined in the statistical analysis plan. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Up to 1.3 years
    End point values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W Pembrolizumab 200mg Q3W
    Number of subjects analysed
    5
    10
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Time to response (TTR) by investigator assessment as per RECIST 1.1

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    End point title
    		 Time to response (TTR) by investigator assessment as per RECIST 1.1
    End point description
    TTR is defined as the time from the date of randomization to the first documented response of either complete response or partial response, which must be subsequently confirmed (although initial date of response is used, not date of confirmation). TTR was analyzed using the Kaplan-Meier method as defined in the statistical analysis plan. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Up to 1.3 years
    End point values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W Pembrolizumab 200mg Q3W
    Number of subjects analysed
    51
    25
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment to 30 days after last dose, up to 2.1 years
    End point values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W Pembrolizumab 200mg Q3W
    Number of subjects analysed
    51
    25
    Units: participants
        AEs
    49
    25
        Treatment-related AEs
    45
    18
        SAEs
    31
    13
        Treatment-related SAEs
    18
    1
        AEs leading to discontinuation
    18
    5
        Treatment-related AEs leading to discontinuation
    17
    2
        AEs leading to dose reduction/interruption
    34
    7
        Treat-rel. AEs leading to dose reduction/interrup.
    24
    2
    No statistical analyses for this end point

    Secondary: Maximum observed plasma concentration (Cmax) of capmatinib

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    End point title
    		 Maximum observed plasma concentration (Cmax) of capmatinib [2]
    End point description
    Pharmacokinetic (PK) parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.
    End point type
    Secondary
    End point timeframe
    pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 2 Day 1. The duration of one cycle was 21 days.
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to capmatinib + pembrolizumab arm
    End point values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W
    Number of subjects analysed
    25
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    2730 ( 155.9 )
    No statistical analyses for this end point

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

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    End point title
    		 Time to reach maximum plasma concentration (Tmax) of capmatinib [3]
    End point description
    PK parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose. Actual recorded sampling times were considered for the calculations.
    End point type
    Secondary
    End point timeframe
    pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 2 Day 1. The duration of one cycle was 21 days.
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to capmatinib + pembrolizumab arm
    End point values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W
    Number of subjects analysed
    25
    Units: hours
        median (full range (min-max))
    1.33 (0 to 4.00)
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of capmatinib

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    End point title
    		 Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of capmatinib [4]
    End point description
    PK parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
    End point type
    Secondary
    End point timeframe
    pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 2 Day 1. The duration of one cycle was 21 days.
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to capmatinib + pembrolizumab arm
    End point values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W
    Number of subjects analysed
    25
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    4210 ( 232.8 )
    No statistical analyses for this end point

    Secondary: Trough serum concentration (Ctrough) of pembrolizumab

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    End point title
    		 Trough serum concentration (Ctrough) of pembrolizumab
    End point description
    PK parameters were calculated based on pembrolizumab serum concentrations by using non-compartmental methods. Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    pre-dose on Cycle 2 Day 1, Cycle 3 Day 1, Cycle 6 Day 1 and Cycle 12 Day 1. The duration of one cycle was 21 days.
    End point values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W Pembrolizumab 200mg Q3W
    Number of subjects analysed
    32
    18
    Units: µg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 2 Day 1 (n=32, 18)
    11.8 ( 37.5 )
    10.6 ( 34.8 )
        Cycle 3 Day 1 (n=29, 18)
    18.9 ( 51.9 )
    18.2 ( 32.3 )
        Cycle 6 Day 1 (n=14, 8)
    27.6 ( 66.5 )
    36.8 ( 26.0 )
        Cycle 12 Day 1 (n=0, 2)
    999 ( 999 )
    49.7 ( 10.0 )
    No statistical analyses for this end point

    Secondary: Number of participants with anti-pembrolizumab antibodies

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    End point title
    		 Number of participants with anti-pembrolizumab antibodies
    End point description
    Immunogenicity (IG) was evaluated in serum samples. The assay to quantify and assess the IG was a validated homogeneous enzyme-linked immunosorbent assay (ELISA). • ADA-negative at baseline: ADA-negative sample at baseline • ADA-positive at baseline: ADA-positive sample at baseline • ADA-negative post-baseline: patient with ADA-negative sample at baseline and at least 1 post baseline determinant sample, all of which are ADA-negative samples • ADA-positive post-baseline: patient with at least 1 ADA-positive sample post baseline
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose), up to 8 months
    End point values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W Pembrolizumab 200mg Q3W
    Number of subjects analysed
    42
    20
    Units: participants
        ADA-negative at baseline
    37
    18
        ADA-positive at baseline
    5
    2
        ADA-negative post-baseline
    36
    18
        ADA-positive post-baseline
    6
    2
    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 were collected from start of treatment to 30 days after last dose. Post-treatment survival follow-up deaths were collected from day 31 after last dose of study treatment until the requirement for survival follow-up was removed following the discontinuation of capmatinib in the combination arm (protocol amendment 03). All deaths refer to the sum of on-treatment deaths plus post-treatment survival follow-up deaths.
    End point type
    Post-hoc
    End point timeframe
    On-treatment: Up to 2.1 years after start of treatment. Post-treatment survival follow-up: Up to 1.3 years after start of treatment.
    End point values
    		 Capmatinib 400mg BID + pembrolizumab 200mg Q3W Pembrolizumab 200mg Q3W
    Number of subjects analysed
    51
    25
    Units: participants
        On-treatment deaths (n=51, 25)
    10
    3
        Post-treatment survival FU deaths (n=38, 20)
    6
    5
        All deaths (n=51, 25)
    16
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment to 30 days after last dose, up to 2.1 years after start of treatment. Patients were analyzed according to the treatment they actually received.
    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
    25.0
    Reporting groups
    Reporting group title
    Capmatinib + pembrolizumab – On-treatment
    Reporting group description
    		 Capmatinib 400 mg BID in combination with pembrolizumab 200 mg Q3W. AEs collected during on-treatment period (up to 30 days after last dose).

    Reporting group title
    Pembrolizumab – On-treatment
    Reporting group description
    		 Pembrolizumab single agent 200 mg Q3W from study start. AEs collected during on-treatment period (up to 30 days after last dose).

    Reporting group title
    Pembrolizumab after combination treatment – On-treatment
    Reporting group description
    		 Pembrolizumab single agent 200 mg Q3W after discontinuing capmatinib. AEs collected during on-treatment period (up to 30 days after last dose).

    Serious adverse events
    		 Capmatinib + pembrolizumab – On-treatment Pembrolizumab – On-treatment Pembrolizumab after combination treatment – On-treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 51 (50.98%)
    13 / 25 (52.00%)
    9 / 51 (17.65%)
         number of deaths (all causes)
    8
    3
    2
         number of deaths resulting from adverse events
    4
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pericardial effusion malignant
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 25 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Vocal cord polyp
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Transaminases increased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radiation pneumonitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anastomotic stenosis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 25 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 25 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 25 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin reaction
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 25 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis listeria
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 25 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 25 (8.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Capmatinib + pembrolizumab – On-treatment Pembrolizumab – On-treatment Pembrolizumab after combination treatment – On-treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 51 (80.39%)
    24 / 25 (96.00%)
    29 / 51 (56.86%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 51 (1.96%)
    6 / 25 (24.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    6
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 51 (7.84%)
    5 / 25 (20.00%)
    1 / 51 (1.96%)
         occurrences all number
    4
    5
    1
    Chest pain
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 25 (12.00%)
    2 / 51 (3.92%)
         occurrences all number
    2
    3
    1
    Fatigue
         subjects affected / exposed
    2 / 51 (3.92%)
    5 / 25 (20.00%)
    3 / 51 (5.88%)
         occurrences all number
    2
    6
    3
    Chills
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 25 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    4
    0
    0
    Oedema peripheral
         subjects affected / exposed
    14 / 51 (27.45%)
    1 / 25 (4.00%)
    6 / 51 (11.76%)
         occurrences all number
    17
    1
    6
    Pyrexia
         subjects affected / exposed
    9 / 51 (17.65%)
    5 / 25 (20.00%)
    2 / 51 (3.92%)
         occurrences all number
    12
    6
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    2
    1
    Productive cough
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 25 (12.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    3
    0
    Cough
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 25 (16.00%)
    3 / 51 (5.88%)
         occurrences all number
    2
    6
    4
    Dyspnoea
         subjects affected / exposed
    5 / 51 (9.80%)
    3 / 25 (12.00%)
    5 / 51 (9.80%)
         occurrences all number
    5
    3
    5
    Haemoptysis
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 25 (8.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    2
    3
    Nasal congestion
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 51 (7.84%)
    4 / 25 (16.00%)
    3 / 51 (5.88%)
         occurrences all number
    4
    5
    3
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    6 / 51 (11.76%)
    1 / 25 (4.00%)
    1 / 51 (1.96%)
         occurrences all number
    7
    1
    1
    Amylase increased
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 25 (8.00%)
    3 / 51 (5.88%)
         occurrences all number
    4
    2
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 51 (9.80%)
    1 / 25 (4.00%)
    0 / 51 (0.00%)
         occurrences all number
    6
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 51 (21.57%)
    3 / 25 (12.00%)
    2 / 51 (3.92%)
         occurrences all number
    13
    3
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    11 / 51 (21.57%)
    3 / 25 (12.00%)
    4 / 51 (7.84%)
         occurrences all number
    12
    3
    2
    Lipase increased
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 25 (8.00%)
    2 / 51 (3.92%)
         occurrences all number
    4
    3
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 25 (8.00%)
    0 / 51 (0.00%)
         occurrences all number
    4
    2
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 25 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    5
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    7 / 51 (13.73%)
    1 / 25 (4.00%)
    1 / 51 (1.96%)
         occurrences all number
    7
    2
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 25 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    1
    0
    4
    SARS-CoV-2 test negative
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 25 (8.00%)
    0 / 51 (0.00%)
         occurrences all number
    6
    3
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 25 (12.00%)
    1 / 51 (1.96%)
         occurrences all number
    3
    3
    2
    Dizziness
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 25 (12.00%)
    1 / 51 (1.96%)
         occurrences all number
    2
    3
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 25 (12.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    3
    0
    Paraesthesia
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 25 (16.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    4
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    3
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 25 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    6
    0
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 25 (4.00%)
    3 / 51 (5.88%)
         occurrences all number
    3
    1
    3
    Abdominal pain
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 25 (8.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    2
    2
    Vomiting
         subjects affected / exposed
    14 / 51 (27.45%)
    2 / 25 (8.00%)
    1 / 51 (1.96%)
         occurrences all number
    18
    4
    1
    Nausea
         subjects affected / exposed
    13 / 51 (25.49%)
    2 / 25 (8.00%)
    1 / 51 (1.96%)
         occurrences all number
    16
    3
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 25 (8.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    2
    0
    Diarrhoea
         subjects affected / exposed
    8 / 51 (15.69%)
    6 / 25 (24.00%)
    4 / 51 (7.84%)
         occurrences all number
    9
    9
    6
    Constipation
         subjects affected / exposed
    5 / 51 (9.80%)
    4 / 25 (16.00%)
    7 / 51 (13.73%)
         occurrences all number
    5
    8
    8
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Ecchymosis
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Dry skin
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 25 (8.00%)
    2 / 51 (3.92%)
         occurrences all number
    1
    4
    2
    Rash
         subjects affected / exposed
    5 / 51 (9.80%)
    3 / 25 (12.00%)
    5 / 51 (9.80%)
         occurrences all number
    7
    6
    7
    Rash maculo-papular
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    4
    0
    Erythema
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Pruritus
         subjects affected / exposed
    5 / 51 (9.80%)
    8 / 25 (32.00%)
    7 / 51 (13.73%)
         occurrences all number
    6
    14
    8
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 25 (4.00%)
    6 / 51 (11.76%)
         occurrences all number
    1
    1
    5
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Myalgia
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 25 (12.00%)
    0 / 51 (0.00%)
         occurrences all number
    4
    4
    0
    Muscular weakness
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    2
    1
    Back pain
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 25 (12.00%)
    2 / 51 (3.92%)
         occurrences all number
    4
    4
    2
    Arthralgia
         subjects affected / exposed
    3 / 51 (5.88%)
    6 / 25 (24.00%)
    5 / 51 (9.80%)
         occurrences all number
    4
    10
    7
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 25 (8.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    5 / 51 (9.80%)
    0 / 25 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    6
    0
    2
    Hypoalbuminaemia
         subjects affected / exposed
    6 / 51 (11.76%)
    2 / 25 (8.00%)
    2 / 51 (3.92%)
         occurrences all number
    7
    2
    2
    Decreased appetite
         subjects affected / exposed
    5 / 51 (9.80%)
    5 / 25 (20.00%)
    2 / 51 (3.92%)
         occurrences all number
    7
    5
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Nov 2019
    The main purpose of this amendment was to address HAs’ requests to provide specific recommendations of concomitant medications to treat diarrhea and nausea toxicities. Free T3 testing was removed from thyroid function monitoring and total T3 was to be tested if abnormal thyroid function was suspected. Unintended references to central ECG monitoring for cardiac toxicity follow up were removed to reflect study conduct.
    17 Feb 2020
    The main purpose of this amendment was to address HAs’ requests to: ● add background clinical pharmacology information for capmatinib, ● exclude subjects with active infection or history of allogeneic tissue/organ transplantation and to provide the recommended treatment modifications for pembrolizumab in details, in order to align with the EU SmPC for pembrolizumab, ● interrupt capmatinib treatment in case of hypersensitivity reactions, as SAEs of hypersensitivity have been reported as suspected to be related to study treatment in the capmatinib IB, ● clarify that SAE reporting is required for any progression of malignancy suspected to be related to study treatment and meeting the SAE definition and ● conduct a safety review by DMC after the first 6 randomized patients have been followed up for at least 6 weeks from randomization or have discontinued earlier. Dose modification guidelines for protocols using capmatinib in combination with PD-1 inhibitors were updated to mandate permanent discontinuation of study treatment in case of myocarditis grade ≥2 or other cardiac event grade ≥3. Further HCV RNA testing was not required if a subject’s HCV Ab test was negative.
    21 Apr 2021
    The main purpose of this amendment was to modify the study conduct and data analysis following the enrollment halt on 21-Jan-2021 due to lack of tolerability observed in the capmatinib plus pembrolizumab arm. The decision to halt enrollment, supported by the DMC, was made based on the observation that subjects who received capmatinib plus pembrolizumab combination treatment had higher rates of SAEs/AEs leading to dose interruption and/or discontinuation of both study treatments compared to subjects in the pembrolizumab single agent arm. Procedural changes included discontinuation of capmatinib treatment in the combination arm, release of randomization to the CTT, termination of PK, biomarker and IG samples. All ongoing subjects continued to receive single-agent pembrolizumab, a registered and commercialized treatment for the study indication. Subjects who remained in the study were allowed to continue receiving pembrolizumab single agent treatment as per investigator’s discretion until unacceptable toxicity, or disease progression, or up to 35 cycles of treatment, whichever occurred first. Treatment beyond disease progression was no longer to be allowed. Other significant changes included: ● All efficacy assessments were performed according to each institution’s standard of care. ● All safety assessments were performed according to each institution’s standard of care. ● Except AEs, efficacy and safety assessment results were not captured in the eCRF. ● End of study definition was refined as the earliest occurrence of discontinuation of study treatment and completed safety follow-up, death or withdrawn consent or lost to follow-up. ● Independent review of safety and efficacy data was no longer required after release of randomization information to the CTT and the DMC was disbanded. ● Originally planned administrative interim analysis was canceled. ● Disease progression follow-up and survival follow-up were not performed.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/#/
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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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