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    Clinical Trial Results:
    A Phase III, Open Label, Randomized Study of AZD9291 versus Platinum-Based Doublet Chemotherapy for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene (AURA3).

    Summary
    EudraCT number
    		 2014-000594-39
    Trial protocol
    		 DE   GB   SE   IT   NL   FR   NO   HU  
    Global end of trial date
    15 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Dec 2024
    First version publication date
    28 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5160C00003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02151981
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca Clinical Study Information Center
    Sponsor organisation address
    Melbourn Science Park, Royston, United Kingdom, SG8 6EE
    Public contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, +1 8772409479, information.center@astrazeneca.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
    Interim
    Date of interim/final analysis
    15 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of Osimertinib compared with platinum-based doublet chemotherapy by assessment of Progression Free Survival using investigator assessment according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1)
    Protection of trial subjects
    Patients given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Aug 2014
    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
    Korea, Republic of: 72
    Country: Number of subjects enrolled
    Japan: 63
    Country: Number of subjects enrolled
    China: 48
    Country: Number of subjects enrolled
    Taiwan: 48
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    United States: 21
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Russian Federation: 16
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Netherlands: 14
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Hong Kong: 12
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Hungary: 1
    Worldwide total number of subjects
    419
    EEA total number of subjects
    83
    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)
    242
    From 65 to 84 years
    174
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient dosed: 20 August 2014. Data cut off: 15 March 2019. Open for enrolment at 145 study centres, 126 centres in 17 countries randomised patients to treatment. Following the final OS analysis, patients were permitted to continue to receive treatment if, in the investigator's opinion, they were continuing to receive benefit from treatment

    Pre-assignment
    Screening details
    		 Consenting subjects were assessed to ensure they met eligibility criteria. Confirmation of T790M mutation assessment was determined by the central laboratory.

    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
    		 Osimertinib 80 mg
    Arm description
    		 Daily single dose of Osimertinib 80mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Osimertinib
    Investigational medicinal product code
    Other name
    AZD9291
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg

    Investigational medicinal product name
    Osimertinib
    Investigational medicinal product code
    Other name
    AZD9291
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    80 mg

    Arm title
    		 Chemotherapy
    Arm description
    		 Platinum-based doublet chemotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pemetrexed + Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pemetrexed 500 mg/m2 on Day 1 of every 21-day cycle Carboplatin AUC5 on Day 1 of every 21-day cycle

    Investigational medicinal product name
    Pemetrexed maintenance monotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2 on Day 1 of every 21-day cycle

    Investigational medicinal product name
    Pemetrexed + Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pemetrexed 500 mg/m2 on Day 1 of every 21-day cycle Cisplatin 75 mg/m2 on Day 1 of every 21-day cycle

    Number of subjects in period 1
    		Osimertinib 80 mg Chemotherapy
    Started
    279
    140
    Received randomised treatment only
    279
    136
    Did not receive treatment
    0 [1]
    4 [2]
    Crossed over Osimertinib
    0 [3]
    99
    Completed
    60
    27
    Not completed
    219
    113
         Adverse event, serious fatal
    184
    88
         Consent withdrawn by subject
    27
    21
         Eligibility criteria not fulfilled
    -
    1
         Other reasons
    1
    2
         Lost to follow-up
    7
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Out of the 136 subjects randomised to the chemotherapy arm, 4 subjects did not receive the study treatment.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only subjects randomised to the chemotherapy arm had the opportunity to cross-over and begin treatment with Osimertinib 80 mg once daily
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Confirms that all 279 subjects randomised to the osimertinib arm received treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Osimertinib 80 mg
    Reporting group description
    		 Daily single dose of Osimertinib 80mg

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Platinum-based doublet chemotherapy

    Reporting group values
    		 Osimertinib 80 mg Chemotherapy Total
    Number of subjects
    		 279 140 419
    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)
    		 165 77 242
        From 65-84 years
    		 113 61 174
        85 years and over
    		 1 2 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 61.5 ( 11.64 ) 62.0 ( 11.91 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 172 97 269
        Male
    		 107 43 150
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 182 92 274
        Black Or African American
    		 4 1 5
        Other
    		 4 1 5
        White
    		 89 45 134
        American Indian or Alaska Native
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Osimertinib 80 mg
    Reporting group description
    		 Daily single dose of Osimertinib 80mg

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Platinum-based doublet chemotherapy

    Primary: Progression Free Survival (PFS) by investigator assessment

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    End point title
    		 Progression Free Survival (PFS) by investigator assessment
    End point description
    Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of randomisation until the date of PD (by investigator assessment) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.
    End point type
    Primary
    End point timeframe
    RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis).
    End point values
    		 Osimertinib 80 mg Chemotherapy
    Number of subjects analysed
    279 [1]
    140 [2]
    Units: Months
        median (confidence interval 95%)
    10.1 (8.3 to 12.3)
    4.4 (4.2 to 5.6)
    Notes
    [1] - 140 events analyzed
    [2] - 110 events analyzed
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    Progression Free Survival (PFS) by investigator assessment
    Comparison groups
    Osimertinib 80 mg v Chemotherapy
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 0.41
    Notes
    [3] - A hazard ratio <1 favours Osimertinib 80mg

    Secondary: Objective Response Rate (ORR) by investigator assessment

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    End point title
    		 Objective Response Rate (ORR) by investigator assessment
    End point description
    Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR prior to progression or any further therapy.
    End point type
    Secondary
    End point timeframe
    RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis).
    End point values
    		 Osimertinib 80 mg Chemotherapy
    Number of subjects analysed
    279
    140
    Units: % of participants
        number (not applicable)
    70.6
    31.4
    Statistical analysis title
    		 Secondary Analysis
    Statistical analysis description
    Objective Response Rate (ORR) by investigator assessment
    Comparison groups
    Osimertinib 80 mg v Chemotherapy
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.47
         upper limit
    		 8.48
    Notes
    [4] - Adjusted for ethnicity (Asian/non-Asian). Adjusted response rate: Osimertinib 72.8, Chemo 33.1

    Secondary: Duration of Response (DoR) by investigator assessment

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    End point title
    		 Duration of Response (DoR) by investigator assessment
    End point description
    Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR is the time from the date of first documented response until the date of documented progression or death in the absence of disease progression.
    End point type
    Secondary
    End point timeframe
    RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis).
    End point values
    		 Osimertinib 80 mg Chemotherapy
    Number of subjects analysed
    279
    140
    Units: months
        median (confidence interval 95%)
    9.7 (8.3 to 11.6)
    4.1 (3.0 to 5.6)
    Statistical analysis title
    		 Secondary Analysis
    Statistical analysis description
    Duration of Response (DoR) by investigator assessment
    Comparison groups
    Osimertinib 80 mg v Chemotherapy
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 < 0.001
    Method
    		 formulae provided in Ellis S et al 2008
    Parameter type
    		 Ratio of Expected (DoR)
    Point estimate
    6.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.04
         upper limit
    		 9.57
    Notes
    [5] - Treatments compared by calculating the ratio of the Expected (DoR) using the Log Normal probability distribution for DOR in responding patients

    Secondary: Disease Control Rate (DCR) by investigator assessment

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    End point title
    		 Disease Control Rate (DCR) by investigator assessment
    End point description
    Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD at >=6 weeks, prior to any progressive disease (PD).
    End point type
    Secondary
    End point timeframe
    RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis).
    End point values
    		 Osimertinib 80 mg Chemotherapy
    Number of subjects analysed
    279
    140
    Units: % of participants
        number (not applicable)
    93.2
    74.3
    Statistical analysis title
    		 Secondary Analysis
    Statistical analysis description
    Disease Control Rate (DCR) by investigator assessment
    Comparison groups
    Osimertinib 80 mg v Chemotherapy
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.64
         upper limit
    		 8.84
    Notes
    [6] - Adjusted response rate: Osimertinib 93.7, Chemo 75.7

    Secondary: Tumour Shrinkage by investigator assessment

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    End point title
    		 Tumour Shrinkage by investigator assessment
    End point description
    Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Tumour size was calculated as the sum of the longest diameters (SLD) of the Target Lesions. Tumour shrinkage is percentage change in tumour size from baseline using RECIST v1.1 tumour response.
    End point type
    Secondary
    End point timeframe
    RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of the primary PFS analysis).
    End point values
    		 Osimertinib 80 mg Chemotherapy
    Number of subjects analysed
    278
    131
    Units: % change from baseline
        arithmetic mean (standard deviation)
    -46.1 ( 29.50 )
    -24.4 ( 29.27 )
    Statistical analysis title
    		 Secondary Analysis
    Statistical analysis description
    Tumour Shrinkage by investigator assessment
    Comparison groups
    Osimertinib 80 mg v Chemotherapy
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS means
    Point estimate
    -21.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.71
         upper limit
    		 -15.52
    Notes
    [7] - Covariates for ethnicity (Asian, non-Asian) and the baseline sum of diameters of target lesions. LS Mean: Osimertinib -46.93, Chemo -25.3 A difference in LS means <0 favours Osimertinib 80mg.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Time between the date of randomisation and the date of death due to any cause
    End point type
    Secondary
    End point timeframe
    From date of randomisation until time of final OS analysis, a median follow-up of 43 months
    End point values
    		 Osimertinib 80 mg Chemotherapy
    Number of subjects analysed
    279 [8]
    140 [9]
    Units: Participants
        Died
    188
    93
        Still in survival follow-up
    58
    27
        Terminated prior to death
    30
    17
        Other
    3
    3
    Notes
    [8] - 188 events analyzed
    [9] - 93 events analyzed
    Statistical analysis title
    		 Secondary Analysis
    Statistical analysis description
    Overall Survival (OS)
    Comparison groups
    Osimertinib 80 mg v Chemotherapy
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.277
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.13
    Notes
    [10] - A hazard ratio <1 favours Osimertinib 80 mg

    Other pre-specified: Time to first subsequent therapy (TFST)

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    End point title
    		 Time to first subsequent therapy (TFST)
    End point description
    Time from randomisation to first subsequent anti-cancer therapy (FST) following randomised treatment discontinuation, or death if no FST administered. Any patient not known to have died nor received any subsequent anti-cancer therapy (ST) was censored at the last time known not to have received ST, ie, the last follow-up visit this was confirmed.
    End point type
    Other pre-specified
    End point timeframe
    From date of randomisation until time of final OS analysis
    End point values
    		 Osimertinib 80 mg Chemotherapy
    Number of subjects analysed
    279 [11]
    140 [12]
    Units: Participants
        Started 1st subsequent cancer therapy
    165
    114
        Did not start 1st subsequent cancer therapy (died)
    65
    14
    Notes
    [11] - 230 events analyzed
    [12] - 128 events analyzed
    Statistical analysis title
    		 Other
    Statistical analysis description
    Time to first subsequent therapy (TFST)
    Comparison groups
    Osimertinib 80 mg v Chemotherapy
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.28
    Notes
    [13] - A hazard ratio <1 favours Osimertinib 80 mg

    Other pre-specified: Time to second subsequent therapy (TSST)

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    End point title
    		 Time to second subsequent therapy (TSST)
    End point description
    Time from randomisation to second subsequent anti-cancer therapy (SST) following randomised treatment discontinuation, or death if no SST administered. Any patient not known to have died nor received any SST was censored at the last time known not to have received SST, ie, the last follow-up visit this was confirmed.
    End point type
    Other pre-specified
    End point timeframe
    From date of randomisation until time of final OS analysis
    End point values
    		 Osimertinib 80 mg Chemotherapy
    Number of subjects analysed
    279 [14]
    140 [15]
    Units: Participants
        Started 2nd subsequent cancer therapy
    108
    52
        Did not start 2nd subsequent cancer therapy (died)
    106
    53
    Notes
    [14] - 214 events analyzed
    [15] - 105 events analyzed
    Statistical analysis title
    		 Other
    Statistical analysis description
    Time to second subsequent therapy (TSST)
    Comparison groups
    Osimertinib 80 mg v Chemotherapy
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.11
    Notes
    [16] - A hazard ratio <1 favours Osimertinib 80 mg

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs from start of study drug until 28 days post treatment discontinuation up to 4 years and 7 months (at the time of analysis)
    Adverse event reporting additional description
    Systematic assessment due to regular investigator assessment at study visits.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Chemotherapy
    Reporting group description
    		 Platinum-based doublet chemotherapy

    Reporting group title
    Osimertinib 80 mg
    Reporting group description
    		 Daily single dose of Osimertinib 80mg

    Serious adverse events
    		 Chemotherapy Osimertinib 80 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 136 (26.47%)
    84 / 279 (30.11%)
         number of deaths (all causes)
    93
    188
         number of deaths resulting from adverse events
    2
    12
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    4 / 136 (2.94%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 136 (1.47%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 136 (1.47%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioratio
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine cyst
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung consolidation
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 136 (0.74%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Dyspnoea
         subjects affected / exposed
    0 / 136 (0.00%)
    4 / 279 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 136 (1.47%)
    8 / 279 (2.87%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 136 (0.00%)
    3 / 279 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Dyspnoea exertional
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric decompensation
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organic brain syndrome
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrin D dimer increased
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharynx radiation injury
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 136 (0.74%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    3 / 136 (2.21%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 136 (0.74%)
    3 / 279 (1.08%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Embolic stroke
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spinal cord compression
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 136 (2.21%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal ischaemia
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 136 (1.47%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 136 (0.74%)
    4 / 279 (1.43%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Dental caries
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematuria
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 136 (0.00%)
    6 / 279 (2.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 136 (1.47%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Chemotherapy Osimertinib 80 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    134 / 136 (98.53%)
    275 / 279 (98.57%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 136 (7.35%)
    9 / 279 (3.23%)
         occurrences all number
    11
    10
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    13 / 136 (9.56%)
    29 / 279 (10.39%)
         occurrences all number
    15
    36
    Oedema peripheral
         subjects affected / exposed
    16 / 136 (11.76%)
    16 / 279 (5.73%)
         occurrences all number
    23
    21
    Non-cardiac chest pain
         subjects affected / exposed
    6 / 136 (4.41%)
    23 / 279 (8.24%)
         occurrences all number
    6
    24
    Malaise
         subjects affected / exposed
    14 / 136 (10.29%)
    12 / 279 (4.30%)
         occurrences all number
    21
    14
    Fatigue
         subjects affected / exposed
    40 / 136 (29.41%)
    54 / 279 (19.35%)
         occurrences all number
    60
    66
    Asthenia
         subjects affected / exposed
    19 / 136 (13.97%)
    23 / 279 (8.24%)
         occurrences all number
    25
    29
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    3 / 136 (2.21%)
    20 / 279 (7.17%)
         occurrences all number
    3
    21
    Dyspnoea
         subjects affected / exposed
    18 / 136 (13.24%)
    35 / 279 (12.54%)
         occurrences all number
    20
    40
    Cough
         subjects affected / exposed
    20 / 136 (14.71%)
    60 / 279 (21.51%)
         occurrences all number
    21
    72
    Productive cough
         subjects affected / exposed
    3 / 136 (2.21%)
    18 / 279 (6.45%)
         occurrences all number
    3
    20
    Rhinorrhoea
         subjects affected / exposed
    2 / 136 (1.47%)
    14 / 279 (5.02%)
         occurrences all number
    2
    18
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 136 (10.29%)
    26 / 279 (9.32%)
         occurrences all number
    16
    28
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    9 / 136 (6.62%)
    16 / 279 (5.73%)
         occurrences all number
    15
    20
    Neutrophil count decreased
         subjects affected / exposed
    16 / 136 (11.76%)
    17 / 279 (6.09%)
         occurrences all number
    38
    31
    Platelet count decreased
         subjects affected / exposed
    21 / 136 (15.44%)
    20 / 279 (7.17%)
         occurrences all number
    34
    32
    Aspartate aminotransferase increased
         subjects affected / exposed
    16 / 136 (11.76%)
    21 / 279 (7.53%)
         occurrences all number
    23
    33
    Alanine aminotransferase increased
         subjects affected / exposed
    17 / 136 (12.50%)
    23 / 279 (8.24%)
         occurrences all number
    25
    34
    Weight decreased
         subjects affected / exposed
    7 / 136 (5.15%)
    16 / 279 (5.73%)
         occurrences all number
    7
    17
    White blood cell count decreased
         subjects affected / exposed
    12 / 136 (8.82%)
    22 / 279 (7.89%)
         occurrences all number
    36
    38
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 136 (11.76%)
    33 / 279 (11.83%)
         occurrences all number
    19
    44
    Dysgeusia
         subjects affected / exposed
    12 / 136 (8.82%)
    9 / 279 (3.23%)
         occurrences all number
    13
    9
    Dizziness
         subjects affected / exposed
    12 / 136 (8.82%)
    22 / 279 (7.89%)
         occurrences all number
    16
    26
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    17 / 136 (12.50%)
    14 / 279 (5.02%)
         occurrences all number
    26
    24
    Leukopenia
         subjects affected / exposed
    7 / 136 (5.15%)
    14 / 279 (5.02%)
         occurrences all number
    12
    33
    Anaemia
         subjects affected / exposed
    35 / 136 (25.74%)
    32 / 279 (11.47%)
         occurrences all number
    45
    38
    Thrombocytopenia
         subjects affected / exposed
    10 / 136 (7.35%)
    18 / 279 (6.45%)
         occurrences all number
    15
    30
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    7 / 136 (5.15%)
    2 / 279 (0.72%)
         occurrences all number
    7
    2
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    8 / 136 (5.88%)
    1 / 279 (0.36%)
         occurrences all number
    10
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    27 / 136 (19.85%)
    42 / 279 (15.05%)
         occurrences all number
    49
    53
    Stomatitis
         subjects affected / exposed
    22 / 136 (16.18%)
    48 / 279 (17.20%)
         occurrences all number
    26
    70
    Diarrhoea
         subjects affected / exposed
    14 / 136 (10.29%)
    123 / 279 (44.09%)
         occurrences all number
    21
    226
    Constipation
         subjects affected / exposed
    48 / 136 (35.29%)
    50 / 279 (17.92%)
         occurrences all number
    94
    56
    Abdominal pain upper
         subjects affected / exposed
    11 / 136 (8.09%)
    10 / 279 (3.58%)
         occurrences all number
    11
    13
    Nausea
         subjects affected / exposed
    66 / 136 (48.53%)
    64 / 279 (22.94%)
         occurrences all number
    144
    75
    Mouth ulceration
         subjects affected / exposed
    0 / 136 (0.00%)
    16 / 279 (5.73%)
         occurrences all number
    0
    26
    Dyspepsia
         subjects affected / exposed
    2 / 136 (1.47%)
    15 / 279 (5.38%)
         occurrences all number
    2
    18
    Abdominal pain
         subjects affected / exposed
    6 / 136 (4.41%)
    20 / 279 (7.17%)
         occurrences all number
    9
    22
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    3 / 136 (2.21%)
    41 / 279 (14.70%)
         occurrences all number
    3
    70
    Skin fissures
         subjects affected / exposed
    1 / 136 (0.74%)
    16 / 279 (5.73%)
         occurrences all number
    1
    18
    Rash maculo-papular
         subjects affected / exposed
    3 / 136 (2.21%)
    19 / 279 (6.81%)
         occurrences all number
    3
    25
    Pruritus
         subjects affected / exposed
    7 / 136 (5.15%)
    42 / 279 (15.05%)
         occurrences all number
    9
    55
    Dry skin
         subjects affected / exposed
    6 / 136 (4.41%)
    54 / 279 (19.35%)
         occurrences all number
    6
    66
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    8 / 136 (5.88%)
    21 / 279 (7.53%)
         occurrences all number
    8
    25
    Back pain
         subjects affected / exposed
    14 / 136 (10.29%)
    42 / 279 (15.05%)
         occurrences all number
    20
    52
    Arthralgia
         subjects affected / exposed
    7 / 136 (5.15%)
    25 / 279 (8.96%)
         occurrences all number
    8
    30
    Musculoskeletal pain
         subjects affected / exposed
    4 / 136 (2.94%)
    21 / 279 (7.53%)
         occurrences all number
    4
    27
    Muscle spasms
         subjects affected / exposed
    2 / 136 (1.47%)
    19 / 279 (6.81%)
         occurrences all number
    2
    22
    Pain in extremity
         subjects affected / exposed
    6 / 136 (4.41%)
    25 / 279 (8.96%)
         occurrences all number
    11
    31
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    6 / 136 (4.41%)
    24 / 279 (8.60%)
         occurrences all number
    9
    32
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 136 (7.35%)
    36 / 279 (12.90%)
         occurrences all number
    10
    61
    Paronychia
         subjects affected / exposed
    2 / 136 (1.47%)
    58 / 279 (20.79%)
         occurrences all number
    2
    72
    Nasopharyngitis
         subjects affected / exposed
    7 / 136 (5.15%)
    34 / 279 (12.19%)
         occurrences all number
    7
    45
    Conjunctivitis
         subjects affected / exposed
    5 / 136 (3.68%)
    14 / 279 (5.02%)
         occurrences all number
    6
    17
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    7 / 136 (5.15%)
    4 / 279 (1.43%)
         occurrences all number
    9
    6
    Decreased appetite
         subjects affected / exposed
    49 / 136 (36.03%)
    67 / 279 (24.01%)
         occurrences all number
    87
    78

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Dec 2014
    V2. Addition post-progression open label Osimertinib for subjects on chemotherapy.
    06 May 2015
    V3. Change the power to detect a statistically significant difference for the primary analysis of progression-free survival (PFS) from 90% to 80%.
    21 Mar 2016
    V4. Additional OS analysis, based on a data cut-off 4 months after the data cut-off for the primary analysis of PFS.
    10 Jan 2017
    V5. Post primary PFS anlysis data collection schedule reduced. Patient management post final OS analysis outlined.

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

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