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    Clinical Trial Results:
    LUX-Lung IO: A phase II, open label, non-randomised study of afatinib in combination with pembrolizumab in patients with locally advanced or metastatic squamous cell carcinoma of the lung

    Summary
    EudraCT number
    		 2016-005042-37
    Trial protocol
    		 ES   FR  
    Global end of trial date
    13 Jan 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    08 Jun 2022
    First version publication date
    06 Jan 2021
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction of previously posted information.

    Trial information

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    Trial identification
    Sponsor protocol code
    1200-0283
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03157089
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany,
    Public contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.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
    21 Feb 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of afatinib in combination with pembrolizumab in patients with locally advanced or metastatic squamous non-small-cell lung cancer (NSCLC) who progressed during or after firstline platinum-based treatment, with efficacy measured by objective response (OR).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all subjects as required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Nov 2017
    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
    France: 6
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Turkey: 4
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    28
    EEA total number of subjects
    18
    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)
    15
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A phase II, open-label, non-randomised, single arm study. Patients with locally advanced or metastatic squamous non-small-cell lung cancer (NSCLC), who progressed during or after first line platinum-based standard therapy and had no prior treatment with an immune checkpoint inhibitor or Epidermal Growth Factor Receptor (EGFR) targeted therapy.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group, if any of the entry criteria were violated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open label trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Afatinib 40 mg + pembrolizumab 200 mg
    Arm description
    		 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.
    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
    200 mg, intravenous infusion, once every 3 weeks.

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Gilotrif®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily.

    Arm title
    		 Afatinib 30 mg + pembrolizumab 200 mg
    Arm description
    		 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.
    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
    200 mg, intravenous infusion, once every 3 weeks.

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Gilotrif®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily.

    Number of subjects in period 1 [1]
    		Afatinib 40 mg + pembrolizumab 200 mg Afatinib 30 mg + pembrolizumab 200 mg
    Started
    12
    12
    Treated with afatinib+pembrolizumab
    12
    12
    Completed
    0
    0
    Not completed
    12
    12
         Adverse event, non-fatal
    5
    4
         Treated only with pembrolizumab
    1
    -
         Progressive disease
    6
    8
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 28 patients had been enrolled, 24 patients thereof were entered into the trial and treated with at least 1 dose of study medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Afatinib 40 mg + pembrolizumab 200 mg
    Reporting group description
    		 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.

    Reporting group title
    Afatinib 30 mg + pembrolizumab 200 mg
    Reporting group description
    		 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.

    Reporting group values
    		 Afatinib 40 mg + pembrolizumab 200 mg Afatinib 30 mg + pembrolizumab 200 mg Total
    Number of subjects
    		 12 12 24
    Age categorical
    Treated Set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
    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)
    		 8 6 14
        From 65-84 years
    		 4 6 10
        85 years and over
    		 0 0 0
    Age Continuous
    Treated Set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
    Units: years
        arithmetic mean (standard deviation)
    		 62.8 ( 10.0 ) 63.3 ( 7.3 ) -
    Sex: Female, Male
    Treated Set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
    Units: Participants
        Female
    		 4 1 5
        Male
    		 8 11 19
    Race (NIH/OMB)
    Treated Set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab. Unknown or Not Reported represents participants from France where information on race could not be collected for legal reasons.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 5 0 5
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 6 8 14
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 1 4 5
    Ethnicity (NIH/OMB)
    Treated Set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab. Ethnicity was not collected.
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 0 0 0
        Unknown or Not Reported
    		 12 12 24

    End points

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    End points reporting groups
    Reporting group title
    Afatinib 40 mg + pembrolizumab 200 mg
    Reporting group description
    		 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.

    Reporting group title
    Afatinib 30 mg + pembrolizumab 200 mg
    Reporting group description
    		 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.

    Primary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [1]
    End point description
    Objective response rate is defined as percentage of participants with best overall response of complete response (CR, disappearance of all target lesions) or confirmed partial response (PR, at least a 30% decrease in sum of diameter (SoD, longest diameter (LD) measured for all lesions except lymph nodes, where shortest diameter (ShD) was used) of target lesions, reference is baseline SoD). Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. The treated set (TS) included all participants who received at least one dose of afatinib or pembrolizumab.
    End point type
    Primary
    End point timeframe
    Tumour assessment performed at screening (-28 days), week 9 (day 56-63) after study treatment (afatinib or pembrolizumab) start and every 9th week thereafter, up to 556 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: 28 patients had been enrolled, 24 patients thereof were entered into the trial and treated with at least 1 doseof study medication.
    End point values
    		 Afatinib 40 mg + pembrolizumab 200 mg Afatinib 30 mg + pembrolizumab 200 mg
    Number of subjects analysed
    12 [2]
    12 [3]
    Units: Percentage of Participants
        number (not applicable)
    16.7
    8.3
    Notes
    [2] - TS
    [3] - TS
    No statistical analyses for this end point

    Secondary: Recommended Phase II Dose (RP2D)

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    End point title
    		 Recommended Phase II Dose (RP2D)
    End point description
    Recommended Phase II Dose (RP2D) was to be calculated through a Bayesian logistic regression model (BLRM) with overdose control that was to be fitted to binary toxicity outcomes. After 12 patients had completed at least one cycle (one cycle equals 21 days and consists of one time infusion of pembrolizumab at Day 1 + daily intake of afatinib) of treatment, the prior distributions were to be updated through Gibbs sampling procedures with the accumulated dose limiting toxicity (DLT) data from the first treatment cycle. The estimate of parameters was to be updated as data were accumulated using the BLRM. At the end of the dose confirmation, the toxicity probability at each dose level was to be calculated to determine an estimate of the RP2D. Posterior probabilities for the rate of DLT were to be summarised from BLRM. Confirmation of the RP2D by the Safety Monitoring Committee (SMC) was to be based on these probabilities as well as on the review of other safety and laboratory data.
    End point type
    Secondary
    End point timeframe
    21 days (1 treatment cycle) from study treatment (afatinib and pembrolizumab) administration.
    End point values
    		 Afatinib 40 mg + pembrolizumab 200 mg Afatinib 30 mg + pembrolizumab 200 mg
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: milligram
        number (not applicable)
    Notes
    [4] - TS, the decision on RP2D was not performed, because the trial was stopped according to the protocol.
    [5] - TS, the decision on RP2D was not performed, because the trial was stopped according to the protocol.
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    Disease control rate was calculated as percentage of participants with CR, PR, or stable disease (SD, neither sufficient shrinkage to qualify for PR, taking as reference the baseline sum of diameters (SoD), nor sufficient increase to qualify for progressive disease (PD, at least a 20% increase in the SoD of target lesions, taking as reference the smallest SoD recorded on study (including baseline), together with an absolute increase in the SoD of at least 5 millimeter (mm ) or the appearance of one or more new lesions). Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. The treated set (TS) included all participants who received at least one dose of afatinib or pembrolizumab.
    End point type
    Secondary
    End point timeframe
    Tumour assessment performed at screening (-28 days), week 9 (day 56-63) after study treatment (afatinib or pembrolizumab) start and every 9th week thereafter, up to 556 days.
    End point values
    		 Afatinib 40 mg + pembrolizumab 200 mg Afatinib 30 mg + pembrolizumab 200 mg
    Number of subjects analysed
    12 [6]
    12 [7]
    Units: Percentage of participants
        number (not applicable)
    50
    58.3
    Notes
    [6] - TS
    [7] - TS
    No statistical analyses for this end point

    Secondary: Duration of objective response (DoR)

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    End point title
    		 Duration of objective response (DoR)
    End point description
    For participants who showed objective response, duration of objective response (DoR), was defined as the time from first documented complete response (CR, disappearance of all target lesions) or partial response (PR, at least a 30% decrease in the sum of diameter (SoD) of target lesions taking as reference the baseline SoD until the earliest of disease progression (PD, at least a 20% increase in the SoD of target lesions, taking as reference the smallest SoD recorded on study (including baseline), together with an absolute increase in the SoD of at least 5 mm or the appearance of one or more new lesions) or death. Tumour response was assessed based on local radiological image (CT or MRI) evaluation by the investigators according to RECIST version 1.1. The number of participants with objective response who experienced the event "disease progression or death (whatever came first)" is reported.
    End point type
    Secondary
    End point timeframe
    Tumour assessment performed at screening (-28 days), week 9 (day 56-63) after study treatment (afatinib or pembrolizumab) start and every 9th week thereafter, up to 436 days.
    End point values
    		 Afatinib 40 mg + pembrolizumab 200 mg Afatinib 30 mg + pembrolizumab 200 mg
    Number of subjects analysed
    2 [8]
    1 [9]
    Units: Participants
    2
    1
    Notes
    [8] - All participants who received at least one dose of study drug and showed objective response.
    [9] - All participants who received at least one dose of study drug and showed objective response.
    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
    Progression-free survival was defined as the time (weeks) from the date of the first afatinib or pembrolizumab administration to the date of disease progression (at least a 20% increase in the sum of diameter (SoD, longest diameter (LD) measured for all lesions except lymph nodes, where shortest diameter (ShD) was used) of target lesions, taking as reference the smallest SoD recorded on study (including baseline), together with an absolute increase in the SoD of at least 5 mm or the appearance of one or more new lesions) or death (if the patient died without progression). The date of progression for the primary analyses was determined based on investigator assessment. Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to RECIST version 1.1. Median and 95% Confidence Interval were calculated using Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    Tumour assessment performed at screening (-28 days), week 9 (day 56-63) after study treatment (afatinib or pembrolizumab) start and every 9th week thereafter, up to 556 days.
    End point values
    		 Afatinib 40 mg + pembrolizumab 200 mg Afatinib 30 mg + pembrolizumab 200 mg
    Number of subjects analysed
    12 [10]
    12 [11]
    Units: weeks
        median (confidence interval 95%)
    9.0 (4.6 to 27.1)
    14.4 (5.0 to 26.1)
    Notes
    [10] - TS, all participants who received at least one dose of afatinib or pembrolizumab.
    [11] - TS, all participants who received at least one dose of afatinib or pembrolizumab.
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Overall survival is defined as the time from the date of treatment start date to the date of death. Participants without event were censored. Median and 95% Confidence Interval were calculated using Kaplan-Meier estimates. The treated set (TS) included all participants who received at least one dose of afatinib or pembrolizumab.
    End point type
    Secondary
    End point timeframe
    From Day 1 of study treatment (afatinib or pembrolizumab) administration up to a total of 574 days.
    End point values
    		 Afatinib 40 mg + pembrolizumab 200 mg Afatinib 30 mg + pembrolizumab 200 mg
    Number of subjects analysed
    12 [12]
    12 [13]
    Units: weeks
        median (confidence interval 95%)
    37.9 (15.0 to 59.3)
    26.6 (8.6 to 53.6)
    Notes
    [12] - TS
    [13] - TS
    No statistical analyses for this end point

    Secondary: Tumour shrinkage

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    End point title
    		 Tumour shrinkage
    End point description
    Tumour shrinkage (in millimeters) is defined as the difference between the minimum post-baseline sum of diameters of target lesions (SoD, longest for non-nodal lesions, short axis for nodal lesions) and the baseline sum of diameters of the same set of target lesions. Tumour shrinkage is reported as percentage change from baseline and represents the maximum decrease or the minimum increase from baseline in SoD in percentage of the baseline SoD. Negative values indicate a reduction in the SoD; positive values indicate an increase in the SoD. Tumour response was assessed based on local radiological image (CT or MRI) evaluation by the investigators according to RECIST 1.1. The treated set (TS) included all participants who received at least one dose of afatinib or pembrolizumab
    End point type
    Secondary
    End point timeframe
    Tumour assessment performed at screening (-28 days), week 9 (day 56-63) after study treatment (afatinib or pembrolizumab) start and every 9th week thereafter, up to 556 days.
    End point values
    		 Afatinib 40 mg + pembrolizumab 200 mg Afatinib 30 mg + pembrolizumab 200 mg
    Number of subjects analysed
    12 [14]
    12 [15]
    Units: Percentage change
        arithmetic mean (standard deviation)
    -7.7 ( 29.83 )
    22.0 ( 71.84 )
    Notes
    [14] - TS
    [15] - TS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    [All-Cause Mortality]: From Day 1 of study treatment administration up to a total of 574 days. [Serious and Other Adverse Events]: From the time of first drug administration up to 558 days.
    Adverse event reporting additional description
    The treated set (TS) included all participants, who received at least one dose of afatinib or pembrolizumab.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Afatinib 30 mg + pembrolizumab 200 mg
    Reporting group description
    		 30 mg of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.

    Reporting group title
    Afatinib 40 mg + pembrolizumab 200 mg
    Reporting group description
    		 40 milligram (mg) of afatinib film-coated tablet, given orally with a glass of water (without food consumption 3 hours (h) prior and 1h post afatinib administration), once daily + pembrolizumab 200 mg, intravenous infusion, once every 3 weeks. Both afatinib and pembrolizumab were to be given until documented disease progression, or unacceptable adverse events, or other reasons requiring treatment discontinuation, or for up to 35 cycles of 21 days (i.e. the approved pembrolizumab monotherapy duration). In case of early discontinuation of one agent, the other agent could be continued as monotherapy for altogether up to 35 cycles.

    Serious adverse events
    		 Afatinib 30 mg + pembrolizumab 200 mg Afatinib 40 mg + pembrolizumab 200 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 12 (75.00%)
    4 / 12 (33.33%)
         number of deaths (all causes)
    10
    10
         number of deaths resulting from adverse events
    0
    1
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Extremity necrosis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated pneumonitis
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Afatinib 30 mg + pembrolizumab 200 mg Afatinib 40 mg + pembrolizumab 200 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    12 / 12 (100.00%)
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Asthenia
         subjects affected / exposed
    3 / 12 (25.00%)
    2 / 12 (16.67%)
         occurrences all number
    5
    2
    Face oedema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Fatigue
         subjects affected / exposed
    4 / 12 (33.33%)
    3 / 12 (25.00%)
         occurrences all number
    6
    6
    Mucosal inflammation
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    Pyrexia
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Vessel puncture site swelling
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Prostatitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Aphonia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Dysphonia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    Dyspnoea
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    3
    2
    Haemoptysis
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Pleuritic pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Restrictive pulmonary disease
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Insomnia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    2
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    4
    Amylase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 12 (25.00%)
         occurrences all number
    2
    10
    Blood creatinine increased
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    International normalised ratio increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Lipase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Transaminases increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    3
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Neuralgia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 12 (25.00%)
    3 / 12 (25.00%)
         occurrences all number
    10
    9
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Cheilitis
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Constipation
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    7 / 12 (58.33%)
    11 / 12 (91.67%)
         occurrences all number
    20
    35
    Dyspepsia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    4 / 12 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    8
    1
    Vomiting
         subjects affected / exposed
    3 / 12 (25.00%)
    3 / 12 (25.00%)
         occurrences all number
    5
    5
    Stomatitis
         subjects affected / exposed
    1 / 12 (8.33%)
    4 / 12 (33.33%)
         occurrences all number
    1
    8
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Cholestasis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Dermatitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Dermatitis acneiform
         subjects affected / exposed
    5 / 12 (41.67%)
    2 / 12 (16.67%)
         occurrences all number
    8
    3
    Dermatitis bullous
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    Pruritus
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    Rash
         subjects affected / exposed
    1 / 12 (8.33%)
    5 / 12 (41.67%)
         occurrences all number
    1
    12
    Xeroderma
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Skin erosion
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Skin exfoliation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    2
    2
    Hypothyroidism
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Back pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    Tendon pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Hepatitis viral
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Paronychia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Pneumonia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    Tracheobronchitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Subcutaneous abscess
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Decreased appetite
         subjects affected / exposed
    3 / 12 (25.00%)
    6 / 12 (50.00%)
         occurrences all number
    3
    7
    Hypercalcaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    Hyperglycaemia
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    Hypomagnesaemia
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Apr 2019
    Safety Monitoring Committee (SMC) recommended after the safety run-in to stop the trial and not open the main part. Modifications in the trial conduct, such as cancellation of the biomarker assessment, modified tumour assessment, Eastern Cooperative Oncology Group (ECOG) performance score evaluation no longer required. New or modified text was introduced in the respective sections of the Clinical Trial Protocol (CTP). After the decision to stop the trial, the definition of the end of the trial was adapted. In addition, new text described that patients were to be discontinued from the trial treatment after completing 35 cycles with pembrolizumab and/or afatinib. Patients were not to be followed up for disease progression or overall survival after discontinuation from trial treatment. Additional information from the Summary of Product Pharacteristics (SmPC) of pembrolizumab was added concerning dose modifications in patients with liver metastases at baseline, myocarditis, and other immune-related Adverse Events (AEs) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3; dose interruption for reasons other than treatment-related AE; supportive care; and management of infusion reaction. Imaging during the trial was clarified.

    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.
    After the safety run-in, the Safety Monitoring Committee (SMC) decided that the benefit-risk ratio was not favorable and recommended stopping the trial. The main part of the trial did not open.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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