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    Clinical Trial Results:
    An open-label, Phase II, single-arm study of everolimus in combination with letrozole in the treatment of postmenopausal women with estrogen receptor positive HER2 negative metastatic or locally advanced breast cancer

    Summary
    EudraCT number
    		 2012-003065-17
    Trial protocol
    		 GB   ES   FR   NL   PT   HU  
    Global end of trial date
    13 Jan 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 Jul 2022
    First version publication date
    28 Jan 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001Y24135
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01698918
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to estimate progression-free survival in patients treated with everolimus + letrozole in the first line setting
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Mar 2013
    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
    Argentina: 6
    Country: Number of subjects enrolled
    France: 39
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Japan: 19
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Portugal: 9
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Thailand: 13
    Country: Number of subjects enrolled
    Turkey: 12
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 52
    Country: Number of subjects enrolled
    Brazil: 21
    Worldwide total number of subjects
    202
    EEA total number of subjects
    65
    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)
    108
    From 65 to 84 years
    93
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted across 52 centers in 13 countries.

    Pre-assignment
    Screening details
    		 A total of 245 participants were screened of which 202 participants were enrolled in the this study to receive study treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Everolimus+letrozole
    Arm description
    		 Participants received everolimus in combination with letrozole as first line treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus was self-administered as a daily dose of 10mg (two 5mg tablets) taken orally continuously until progression of disease, unacceptable toxicity or withdrawal of consent. Everolimus in combination with letrozole was offered as the first line treatment.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Femara
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole was self administered as a daily dose of 2.5mg continuously until disease progression or any other reason for which the patient might be discontinued. Everolimus in combination with letrozole was offered as the first line treatment.

    Arm title
    		 Everolimus+exemestane
    Arm description
    		 Participants who had disease progression in the first line setting (core phase) were offered second-line treatment (everolimus in combination with exemestane)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Aromasin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane was self administered as a daily dose of 25mg taken orally continuously until disease progression or any other reason for which the patient might be discontinued. Everolimus in combination with exemestane was offered as the second-line treatment (participants who had disease progression in first line setting).

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus was self-administered as a daily dose of 10mg (two 5mg tablets) taken orally continuously until progression of disease, unacceptable toxicity or withdrawal of consent. Everolimus in combination with exemestane was offered as the second-line treatment (participants who had disease progression in first line setting).

    Number of subjects in period 1
    		Everolimus+letrozole Everolimus+exemestane
    Started
    202
    53
    Completed
    29
    7
    Not completed
    173
    46
         Adverse event, serious fatal
    2
    1
         Consent withdrawn by subject
    11
    1
         Physician decision
    7
    3
         Disease progression
    120
    38
         Adverse event, non-fatal
    33
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus+letrozole
    Reporting group description
    		 Participants received everolimus in combination with letrozole as first line treatment.

    Reporting group title
    Everolimus+exemestane
    Reporting group description
    		 Participants who had disease progression in the first line setting (core phase) were offered second-line treatment (everolimus in combination with exemestane)

    Reporting group values
    		 Everolimus+letrozole Everolimus+exemestane Total
    Number of subjects
    		 202 53 202
    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)
    		 108 37 108
        From 65-84 years
    		 93 16 93
        85 years and over
    		 1 0 1
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 63.5 ( 8.75 ) 60.8 ( 8.90 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 202 53 202
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 146 32 146
        Black
    		 7 2 7
        Asian
    		 44 17 44
        Pacific islander
    		 1 1 1
        Other
    		 4 1 4

    End points

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    End points reporting groups
    Reporting group title
    Everolimus+letrozole
    Reporting group description
    		 Participants received everolimus in combination with letrozole as first line treatment.

    Reporting group title
    Everolimus+exemestane
    Reporting group description
    		 Participants who had disease progression in the first line setting (core phase) were offered second-line treatment (everolimus in combination with exemestane)

    Subject analysis set title
    Everolimus+letrozole (first-line treatment)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received everolimus in combination with letrozole as first-line treatment

    Subject analysis set title
    Everolimus+letrozole (first line treatment)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received everolimus in combination with letrozole as first-line treatment

    Subject analysis set title
    Everolimus+exemestane (second line treatment)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who had disease progression in the first line setting (core phase) treated with second line treatment (everolimus in combination with exemestane)

    Subject analysis set title
    Everolimus+exemestane (second-line treatment)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who had disease progression in the first line setting (core phase) treated with second-line treatment (everolimus in combination with exemestane)

    Subject analysis set title
    Everolimus+letrozole (first-line treatment)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received everolimus in combination with letrozole as first-line treatment

    Subject analysis set title
    Everolimus+letrozole (first line treatment)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received everolimus in combination with letrozole as first line treatment

    Subject analysis set title
    Everolimus+letrozole (first line treatment)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received everolimus in combination with letrozole as first-line treatment

    Subject analysis set title
    Everolimus+ letrozole (first-line treatment)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received everolimus in combination with letrozole as first-line treatment

    Subject analysis set title
    Everolimus+letrozole (first-line treatment)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received everolimus in combination with letrozole as first-line treatment

    Subject analysis set title
    Everolimus+letrozole (first-line treatment)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received everolimus in combination with letrozole as first-line treatment.

    Subject analysis set title
    Everolimus+exemestane (second-line treatment)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who had disease progression in the first line setting (core phase) treated with second-line treatment (everolimus in combination with exemestane)

    Subject analysis set title
    Everolimus+letrozole/exemestane
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received everolimus in combination with letrozole as first line treatment. Only participants who had disease progression in the first line setting (core phase) were offered second-line treatment (everolimus in combination with exemestane)

    Primary: First-line treatment: Progression-free survival (PFS)

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    End point title
    		 First-line treatment: Progression-free survival (PFS) [1]
    End point description
    PFS in the first line setting is defined as the time from the date of enrollment to the date of first documented progression based on local radiology review or death due to any cause. If a participant did not progress or was not known to have died at the date of the analysis cut-off or start of another antineoplastic therapy, the PFS date was censored to the date of last adequate tumor assessment prior to cut-off date or start of antineoplastic therapy. The median PFS was estimated and presented along with 95% confidence intervals. The primary analysis of PFS for first line was performed 12 months after the last patient's recruitment.
    End point type
    Primary
    End point timeframe
    From the date of enrollment to the date of first documented progression or deaths, assessed up to approximately 2.8 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for the primary endpoint
    End point values
    		 Everolimus+letrozole (first-line treatment)
    Number of subjects analysed
    202
    Units: Months
        median (confidence interval 95%)
    999 (18.0 to 999)
    No statistical analyses for this end point

    Secondary: First-line treatment: Overall response rate (ORR)

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    End point title
    		 First-line treatment: Overall response rate (ORR)
    End point description
    ORR in first line setting is defined as the percentage of participants while on first-line treatment with best overall response of complete response (CR) or partial response (PR) according to RECIST version 1.0 based on local review. Confidence intervals were calculated based on the Exact Clopper-Pearson method. ORR while on first-line treatment was assessed up to 24 months after the last patient's recruitment. CR: disappearance of all target lesions PR: at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.
    End point type
    Secondary
    End point timeframe
    From the date of enrollment up to approximately 3.8 years
    End point values
    		 Everolimus+letrozole (first line treatment)
    Number of subjects analysed
    202
    Units: Percentage of participants
        number (confidence interval 95%)
    45.0 (38.1 to 52.2)
    No statistical analyses for this end point

    Secondary: First-line treatment: Clinical benefit rate (CBR)

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    End point title
    		 First-line treatment: Clinical benefit rate (CBR)
    End point description
    CBR in first line is defined as the percentage of participants while on first-line treatment with best overall response of CR, PR or stable disease (SD) with a duration of 24 weeks or longer, according to RECIST version 1.0 based on local review. Confidence intervals (CI) were calculated based on the Exact Clopper-Pearson method. CBR while on first-line treatment was assessed up to 24 months after the last patient's recruitment. CR: disappearance of all target lesions PR: at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease
    End point type
    Secondary
    End point timeframe
    From the date of enrollment up to approximately 3.8 years
    End point values
    		 Everolimus+letrozole (first-line treatment)
    Number of subjects analysed
    202
    Units: Percentage of participants
        number (confidence interval 95%)
    74.3 (67.7 to 80.1)
    No statistical analyses for this end point

    Secondary: Second-line treatment: Progression-free survival (PFS)

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    End point title
    		 Second-line treatment: Progression-free survival (PFS)
    End point description
    PFS in the second line setting is defined as the time interval between the start of the second-line treatment and documented disease progression based on local radiology review or death due to any cause reported during or after second-line treatment period. If a participant did not progress or was not known to have died at the date of the analysis cut-off or start of another antineoplastic therapy, the PFS date was censored to the date of last adequate tumor assessment prior to cut-off date or start of antineoplastic therapy. The median PFS was estimated and presented along with 95% confidence intervals. PFS while on second-line treatment was assessed up to 24 months after the last patient's recruitment.
    End point type
    Secondary
    End point timeframe
    From the start of the second-line treatment to the date of first documented progression or death, assessed up to approximately 2.4 years
    End point values
    		 Everolimus+exemestane (second line treatment)
    Number of subjects analysed
    50
    Units: Months
        median (confidence interval 95%)
    3.7 (1.9 to 7.4)
    No statistical analyses for this end point

    Secondary: Second-line treatment: Overall response rate (ORR)

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    End point title
    		 Second-line treatment: Overall response rate (ORR)
    End point description
    ORR in second line is defined as the percentage of participants receiving second-line study treatment with best overall response of complete response (CR) or partial response (PR) according to RECIST version 1.0 based on local review. Confidence intervals (CI) were calculated based on the Exact Clopper-Pearson method. ORR while on second-line treatment was assessed up to 24 months after the last patient's recruitment. CR: disappearance of all target lesions PR: at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters
    End point type
    Secondary
    End point timeframe
    From the start of the second-line treatment up to approximately 2.4 years
    End point values
    		 Everolimus+exemestane (second-line treatment)
    Number of subjects analysed
    50
    Units: Percentage of participants
        number (confidence interval 95%)
    6.0 (1.3 to 16.5)
    No statistical analyses for this end point

    Secondary: Second-line treatment: Clinical benefit rate (CBR)

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    End point title
    		 Second-line treatment: Clinical benefit rate (CBR)
    End point description
    CBR in second line is defined as the percentage of participants receiving second-line study treatment with best overall response of CR, PR or stable disease (SD) with a duration of 24 weeks or longer, according to RECIST version 1.0 based on local review. Confidence intervals (CI) were calculated based on the Exact Clopper-Pearson method. CBR while on second-line treatment was assessed up to 24 months after the last patient's recruitment. CR: disappearance of all target lesions PR: at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease
    End point type
    Secondary
    End point timeframe
    From the start of the second-line treatment up to approximately 2.4 years
    End point values
    		 Everolimus+exemestane (second-line treatment)
    Number of subjects analysed
    50
    Units: Percentage of participants
        number (confidence interval 95%)
    28.0 (16.2 to 42.5)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS following first-line treatment with everolimus + letrozole is defined as the time from the date of receiving first line study treatment to date of death due to any cause (including first-line and second-line treatment periods). If a participant was not known to have died, survival was censored at the date of last contact. OS following first-line treatment was assessed up to 24 months after last patient's recruitment.
    End point type
    Secondary
    End point timeframe
    From the date of receiving first-line study treatment to date of death, assessed up to approximately 3.8 years
    End point values
    		 Everolimus+letrozole/exemestane
    Number of subjects analysed
    202
    Units: Months
        median (confidence interval 95%)
    999 (37.0 to 999)
    No statistical analyses for this end point

    Secondary: First-line treatment: Time to first stomatitis episode as assessed by the Oral Stomatitis Daily Questionnaire (OSDQ)

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    End point title
    		 First-line treatment: Time to first stomatitis episode as assessed by the Oral Stomatitis Daily Questionnaire (OSDQ)
    End point description
    The time to first occurrence of stomatitis based on OSDQ is defined as time from first-line treatment administration to start date of the stomatitis episode recorded in the OSDQ in the first line. The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The first item asked the participants when they experienced the first symptoms of stomatitis. Start date of the first occurrence of stomatitis is defined as the first date ever recorded for this item in the questionnaire. Patient reported outcomes (PROs) were assessed up to 24 months after last patient's recruitment.
    End point type
    Secondary
    End point timeframe
    From first-line treatment administration until first stomatitis episode in the first line, assessed up to approximately 3.8 years
    End point values
    		 Everolimus+letrozole (first-line treatment)
    Number of subjects analysed
    92
    Units: Weeks
        median (confidence interval 95%)
    1.7 (1.3 to 2.1)
    No statistical analyses for this end point

    Secondary: First-line treatment: Duration of first stomatitis based on OSDQ

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    End point title
    		 First-line treatment: Duration of first stomatitis based on OSDQ
    End point description
    The duration of the first stomatitis episode was calculated using the start and end date recorded in the OSDQ. The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis. The first item of the questionnaire asked the participants the date when they experienced the first symptoms of stomatitis. Start date of the first occurrence of stomatitis is defined as the first date ever recorded for this item in the questionnaire. Stop date of the first stomatitis episode is defined as the last date the OSDQ was completed for this episode. Participants were censored if they died before resolution of stomatitis, received a new anticancer therapy, discontinued the study treatment with no resolution of the stomatitis or the stomatitis event was still on-going at the cut-off. PROs were assessed up to 24 months after last patient's recruitment.
    End point type
    Secondary
    End point timeframe
    From start date of first stomatitis episode in first line until its resolution, assessed up to 3.8 years
    End point values
    		 Everolimus+letrozole (first-line treatment)
    Number of subjects analysed
    92
    Units: Weeks
        median (confidence interval 95%)
    12.3 (4.1 to 23.1)
    No statistical analyses for this end point

    Secondary: First-line treatment: Number of participants with shift of response in OSDQ score on overall health at the end of the first stomatitis episode

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    End point title
    		 First-line treatment: Number of participants with shift of response in OSDQ score on overall health at the end of the first stomatitis episode
    End point description
    The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily up to the resolution of the stomatitis episode. The second item asked the participant to rate their overall health from 0 (worst possible) to 10 (perfect health). The overall health OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
    End point type
    Secondary
    End point timeframe
    From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
    End point values
    		 Everolimus+letrozole (first-line treatment)
    Number of subjects analysed
    92
    Units: Participants
        From 0 to 0
    2
        From 0 to 1
    1
        From 0 to 5
    1
        From 1 to 1
    1
        From 1 to 2
    1
        From 2 to 5
    1
        From 2 to 8
    2
        From 3 to 0
    1
        From 3 to 3
    3
        From 3 to 5
    2
        From 3 to 10
    2
        From 4 to 3
    2
        From 4 to 5
    1
        From 4 to 7
    1
        From 4 to 8
    2
        From 5 to 0
    1
        From 5 to 3
    3
        From 5 to 4
    1
        From 5 to 5
    7
        From 5 to 6
    4
        From 5 to 7
    3
        From 5 to 9
    1
        From 5 to 10
    2
        From 6 to 5
    2
        From 6 to 6
    3
        From 6 to 7
    2
        From 6 to 9
    2
        From 7 to 3
    2
        From 7 to 4
    1
        From 7 to 5
    1
        From 7 to 7
    3
        From 7 to 9
    1
        From 8 to 1
    1
        From 8 to 7
    1
        From 8 to 8
    4
        From 8 to 9
    5
        From 8 to 10
    2
        From 9 to 0
    1
        From 9 to 4
    2
        From 9 to 8
    1
        From 9 to 9
    8
        From 10 to 3
    1
        From 10 to 9
    1
        From missing value to missing value
    3
    No statistical analyses for this end point

    Secondary: First-line treatment: Number of participants with shift of response in OSDQ score on mouth and throat soreness at the end of the first stomatitis episode

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    End point title
    		 First-line treatment: Number of participants with shift of response in OSDQ score on mouth and throat soreness at the end of the first stomatitis episode
    End point description
    The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The third item asked the participant to rate their mouth and throat soreness from 0 (no soreness) to 4 (extreme soreness). The mouth and throat soreness OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
    End point type
    Secondary
    End point timeframe
    From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
    End point values
    		 Everolimus+letrozole (first line treatment)
    Number of subjects analysed
    92
    Units: Participants
        From 0 to 0
    3
        From 1 to 0
    22
        From 1 to 1
    12
        From 1 to 2
    3
        From 2 to 0
    13
        From 2 to 1
    7
        From 2 to 2
    4
        From 2 to 3
    1
        From 3 to 0
    9
        From 3 to 1
    4
        From 3 to 2
    5
        From 3 to 3
    1
        From 3 to 4
    1
        From 4 to 1
    2
        From 4 to 2
    1
        From missing value to missing value
    4
    No statistical analyses for this end point

    Secondary: First-line treatment: Number of participants with shift of response in OSDQ score on mouth and throat soreness limiting swallowing, drinking, eating, talking and sleeping at the end of the first stomatitis episode

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    End point title
    		 First-line treatment: Number of participants with shift of response in OSDQ score on mouth and throat soreness limiting swallowing, drinking, eating, talking and sleeping at the end of the first stomatitis episode
    End point description
    The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The fourth item asked the participant to rate how much their mouth and throat soreness limited them in 1) swallowing, 2) drinking, 3) eating, 4) talking and 5) sleeping. For each activity, mouth and throat soreness scores ranged from 0 (not limited) to 4 (unable to do). Scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
    End point type
    Secondary
    End point timeframe
    From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
    End point values
    		 Everolimus+letrozole (first line treatment)
    Number of subjects analysed
    92
    Units: Participants
        Swallowing: From 0 to 0
    40
        Swallowing: From 0 to 1
    3
        Swallowing: From 0 to 2
    1
        Swallowing: From 1 to 0
    7
        Swallowing: From 1 to 1
    6
        Swallowing: From 1 to 2
    3
        Swallowing: From 1 to 3
    1
        Swallowing: From 2 to 0
    6
        Swallowing: From 2 to 1
    4
        Swallowing: From 2 to 2
    2
        Swallowing: From 3 to 0
    8
        Swallowing: From 3 to 1
    2
        Swallowing: From 3 to 3
    2
        Swallowing: From missing value to missing value
    7
        Drinking: From 0 to 0
    48
        Drinking: From 0 to 1
    4
        Drinking: From 0 to 2
    1
        Drinking: From 1 to 0
    10
        Drinking: From 1 to 1
    5
        Drinking: From 1 to 2
    1
        Drinking: From 2 to 0
    4
        Drinking: From 2 to 1
    3
        Drinking: From 2 to 2
    3
        Drinking: From 2 to 3
    2
        Drinking: From 3 to 0
    6
        Drinking: From 3 to 1
    1
        Drinking: From 3 to 3
    1
        Drinking: From missing value to missing value
    9
        Eating: From 0 to 0
    17
        Eating: From 0 to 1
    2
        Eating: From 0 to 2
    1
        Eating: From 1 to 0
    14
        Eating: From 1 to 1
    11
        Eating: From 1 to 2
    2
        Eating: From 2 to 0
    8
        Eating: From 2 to 1
    3
        Eating: From 2 to 2
    4
        Eating: From 2 to 3
    2
        Eating: From 3 to 0
    7
        Eating: From 3 to 1
    6
        Eating: From 3 to 2
    3
        Eating: From 3 to 3
    4
        Eating: From 4 to 1
    1
        Eating: From missing value to missing value
    7
        Talking: From 0 to 0
    45
        Talking: From 0 to 1
    5
        Talking: From 1 to 0
    12
        Talking: From 1 to 1
    2
        Talking: From 2 to 0
    5
        Talking: From 2 to 1
    2
        Talking: From 2 to 2
    3
        Talking: From 2 to 3
    1
        Talking: From 3 to 0
    4
        Talking: From 3 to 2
    1
        Talking: From 3 to 3
    3
        Talking: From missing value to missing value
    9
        Sleeping: From 0 to 0
    48
        Sleeping: From 0 to 1
    4
        Sleeping: From 0 to 2
    1
        Sleeping: From 1 to 0
    8
        Sleeping: From 1 to 1
    2
        Sleeping: From 1 to 2
    2
        Sleeping: From 2 to 0
    4
        Sleeping: From 2 to 1
    3
        Sleeping: From 2 to 2
    6
        Sleeping: From 3 to 0
    1
        Sleeping: From 3 to 1
    1
        Sleeping: From 3 to 2
    1
        Sleeping: From missing value to missing value
    11
    No statistical analyses for this end point

    Secondary: First-line treatment: Number of participants with shift of response in OSDQ score on mouth pain severity at the end of the first stomatitis episode

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    End point title
    		 First-line treatment: Number of participants with shift of response in OSDQ score on mouth pain severity at the end of the first stomatitis episode
    End point description
    The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The fifth item asked the participant to rate their mouth pain severity from 0 (no pain) to 10 (unbearable pain). The mouth pain severity OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
    End point type
    Secondary
    End point timeframe
    From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
    End point values
    		 Everolimus+letrozole (first-line treatment)
    Number of subjects analysed
    92
    Units: Participants
        From 0 to 0
    5
        From 1 to 0
    10
        From 1 to 1
    6
        From 1 to 2
    1
        From 1 to 3
    1
        From 1 to 5
    1
        From 2 to 0
    6
        From 2 to 3
    1
        From 3 to 0
    7
        From 3 to 1
    1
        From 3 to 2
    2
        From 3 to 3
    1
        From 3 to 4
    2
        From 4 to 0
    4
        From 4 to 1
    2
        From 4 to 4
    1
        From 4 to 5
    1
        From 5 to 0
    3
        From 5 to 1
    1
        From 5 to 2
    1
        From 5 to 3
    1
        From 5 to 4
    1
        From 5 to 5
    1
        From 5 to 6
    1
        From 5 to 7
    1
        From 5 to 10
    1
        From 6 to 0
    2
        From 6 to 1
    1
        From 6 to 2
    1
        From 6 to 5
    1
        From 6 to 6
    1
        From 6 to 8
    1
        From 7 to 0
    2
        From 7 to 1
    2
        From 7 to 2
    1
        From 7 to 7
    1
        From 8 to 0
    3
        From 8 to 2
    1
        From 8 to 4
    2
        From 8 to 5
    1
        From 8 to 6
    1
        From 8 to 9
    1
        From 9 to 0
    2
        From 9 to 9
    1
        From missing value to missing value
    4
    No statistical analyses for this end point

    Secondary: First-line treatment: Number of participants with shift of response in OSDQ score on mouth pain severity affecting daily activities at the end of the first stomatitis episode

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    End point title
    		 First-line treatment: Number of participants with shift of response in OSDQ score on mouth pain severity affecting daily activities at the end of the first stomatitis episode
    End point description
    The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The sixth item asked the participant to rate their mouth pain severity affecting daily activities score from 0 (no effect on daily activities) to 10 (completely prevented from doing daily activities). The mouth pain severity affecting daily activities OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment.
    End point type
    Secondary
    End point timeframe
    From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
    End point values
    		 Everolimus+letrozole (first-line treatment)
    Number of subjects analysed
    92
    Units: Participants
        From 0 to 0
    33
        From 0 to 1
    1
        From 0 to 5
    1
        From 1 to 0
    7
        From 1 to 1
    4
        From 1 to 4
    2
        From 2 to 0
    6
        From 2 to 1
    1
        From 2 to 2
    3
        From 2 to 3
    1
        From 2 to 4
    1
        From 3 to 0
    3
        From 3 to 1
    3
        From 3 to 2
    1
        From 3 to 3
    1
        From 3 to 4
    1
        From 4 to 0
    2
        From 5 to 0
    2
        From 5 to 1
    1
        From 5 to 2
    1
        From 5 to 3
    1
        From 5 to 5
    1
        From 5 to 6
    1
        From 6 to 1
    1
        From 6 to 5
    1
        From 6 to 8
    1
        From 7 to 0
    1
        From 8 to 0
    1
        From 8 (to 8
    1
        From 8 to 10
    1
        From 9 to 0
    1
        From 9 to 8
    1
        From 10 to 10
    1
        From missing value to missing value
    4
    No statistical analyses for this end point

    Secondary: First-line treatment (stomatitis sub-study): Duration of first stomatitis based on OSDQ

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    End point title
    		 First-line treatment (stomatitis sub-study): Duration of first stomatitis based on OSDQ
    End point description
    The duration of the first stomatitis was calculated using the start and end date reported in the OSDQ. The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis. The first item asked the participants the date when they experienced the first symptoms of stomatitis. Start date of the first stomatitis is defined as the first date ever recorded for this item in the questionnaire. Stop date of the first stomatitis is defined as the last date the OSDQ was completed for this episode. Participants were censored if they died before resolution of stomatitis, received a new anticancer therapy, discontinued the study treatment with no resolution of the stomatitis or the stomatitis was still on-going at the cut-off. PROs were assessed up to 24 months after last patient's recruitment. Only participants who were randomized in the stomatitis sub-study were included in this analysis.
    End point type
    Secondary
    End point timeframe
    From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
    End point values
    		 Everolimus+letrozole (first-line treatment)
    Number of subjects analysed
    24
    Units: Weeks
    median (confidence interval 95%)
        Dexamethasone
    999 (999 to 999)
        Standard of Care
    13.7 (1.4 to 13.7)
    No statistical analyses for this end point

    Secondary: First-line treatment (stomatitis sub-study): Time to first stomatitis episode as assessed by the OSDQ

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    End point title
    		 First-line treatment (stomatitis sub-study): Time to first stomatitis episode as assessed by the OSDQ
    End point description
    The time to first occurrence of stomatitis based on OSDQ is defined as time from first study treatment administration in the first line to start date of the first stomatitis episode recorded in the OSDQ. The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The first item asked the participants when they experienced the first symptoms of stomatitis. Start date of the first occurrence of stomatitis is defined as the first date ever recorded for this item in the questionnaire. PROs were assessed up to 24 months after last patient's recruitment. Only participants who were randomized in the stomatitis sub-study were included in this analysis.
    End point type
    Secondary
    End point timeframe
    From first study treatment administration in the first line until first stomatitis episode, assessed up to approximately 3.8 years
    End point values
    		 Everolimus+ letrozole (first-line treatment)
    Number of subjects analysed
    24
    Units: Weeks
    median (confidence interval 95%)
        Dexamethasone
    1.4 (0.9 to 1.9)
        Standard of care
    2.3 (0.7 to 5.4)
    No statistical analyses for this end point

    Secondary: First-line treatment (stomatitis sub-study): Number of participants with shift of response in OSDQ score on overall health at the end of the first stomatitis episode

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    End point title
    		 First-line treatment (stomatitis sub-study): Number of participants with shift of response in OSDQ score on overall health at the end of the first stomatitis episode
    End point description
    The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The second item asked the participant to rate their overall health from 0 (worst possible) to 10 (perfect health). The overall health OSDQ score are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment. Only participants who were randomized in the stomatitis sub-study were included in this analysis.
    End point type
    Secondary
    End point timeframe
    From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
    End point values
    		 Everolimus+letrozole (first-line treatment)
    Number of subjects analysed
    24
    Units: Participants
        Dexamethasone: From 2 to 5
    1
        Dexamethasone: From 4 to 3
    1
        Dexamethasone: From 5 to 5
    1
        Dexamethasone: From 5 to 6
    1
        Dexamethasone: From 5 to 7
    1
        Dexamethasone: From 6 to 5
    1
        Dexamethasone: From 6 to 7
    1
        Dexamethasone: From 7 to 3
    1
        Dexamethasone: From 8 to 8
    1
        Dexamethasone: From 8 to 9
    1
        Dexamethasone: From 9 to 9
    1
        SoC: From 0 to 5
    1
        SoC: From 4 to 3
    1
        SoC: From 4 to 8
    1
        SoC: From 5 to 5
    1
        SoC: From 6 to 7
    1
        SoC: From 7 to 3
    1
        SoC: From 8 to 9
    1
        SoC: From 8 to 10
    1
        SoC: From 9 to 4
    1
        SoC: From 9 to 9
    2
        SoC: From missing value to missing value
    2
    No statistical analyses for this end point

    Secondary: First-line treatment (stomatitis sub-study): Number of participants with shift of response in OSDQ score on mouth and throat soreness at the end of the first stomatitis episode

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    End point title
    		 First-line treatment (stomatitis sub-study): Number of participants with shift of response in OSDQ score on mouth and throat soreness at the end of the first stomatitis episode
    End point description
    The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The third item asked the participant to rate their mouth and throat soreness from 0 (no soreness) to 4 (extreme soreness). The mouth and throat soreness OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment. Only participants who were randomized in the stomatitis sub-study were included in this analysis.
    End point type
    Secondary
    End point timeframe
    From start date of stomatitis episode until its resolution, assessed up to 3.8 years
    End point values
    		 Everolimus+letrozole (first-line treatment)
    Number of subjects analysed
    24
    Units: Participants
        Dexamethasone: From 0 to 0
    1
        Dexamethasone: From 1 to 0
    3
        Dexamethasone: From 1 to 1
    2
        Dexamethasone: From 2 to 0
    1
        Dexamethasone: From 2 to 1
    3
        Dexamethasone: From 3 to 1
    1
        SoC: From 1 to 0
    1
        SoC: From 1 to 1
    1
        SoC: From 2 to 1
    1
        SoC: From 3 to 0
    2
        SoC: From 3 to 1
    1
        SoC: From 3 to 2
    3
        SoC: From 4 to 1
    1
        SoC: From 4 to 2
    1
        SoC: From missing value to missing value
    2
    No statistical analyses for this end point

    Secondary: First-line treatment (stomatitis sub-study): Number of participants with shift of response in OSDQ score on mouth and throat soreness limiting swallowing, drinking, eating, talking and sleeping at the end of the first stomatitis episode

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    End point title
    		 First-line treatment (stomatitis sub-study): Number of participants with shift of response in OSDQ score on mouth and throat soreness limiting swallowing, drinking, eating, talking and sleeping at the end of the first stomatitis episode
    End point description
    The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The fourth item asked the participant to rate how much their mouth and throat soreness limited them in 1) swallowing, 2) drinking, 3) eating, 4) talking and 5) sleeping. For each activity, mouth and throat soreness scores ranged from 0 (not limited) to 4 (unable to do). Scores are presented as the shift from Day 1 of first stomatitis stomatitis value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first episode value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment. Only participants who were randomized in the stomatitis sub-study were included in this analysis.
    End point type
    Secondary
    End point timeframe
    From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
    End point values
    		 Everolimus+letrozole (first-line treatment)
    Number of subjects analysed
    24
    Units: Participants
        Swallowing (dexamethasone): From 0 to 0
    6
        Swallowing (dexamethasone): From 1 to 0
    2
        Swallowing (dexamethasone): From 1 to 2
    1
        Swallowing (dexamethasone): From 2 to 0
    1
        Swallowing (dexamethasone): From 2 to 2
    1
        Swallowing (SoC): From 0 to 0
    5
        Swallowing (SoC): From 1 to 2
    1
        Swallowing (SoC): From 2 to 0
    1
        Swallowing (SoC): From 2 to 1
    2
        Swallowing (SoC): From 3 to 0
    1
        Swallowing (SoC): From 3 to 1
    1
        Swallowing(SoC)From missing value to missing value
    2
        Drinking (dexamethasone): From 0 to 0
    6
        Drinking (dexamethasone): From 1 to 0
    2
        Drinking (dexamethasone): From 1 to 1
    1
        Drinking (dexamethasone): From 2 to 0
    1
        Drinking (dexamethasone): From 2 to 2
    1
        Drinking (SoC): From 0 to 0
    3
        Drinking (SoC): From 0 to 1
    2
        Drinking (SoC): From 2 to 0
    3
        Drinking (SoC): From 2 to 1
    1
        Drinking (SoC): From 3 to 0
    1
        Drinking (SoC): From 3 to 1
    1
        Drinking(SoC):From missing value to missing value
    2
        Eating (dexamethasone): From 0 to 0
    3
        Eating (dexamethasone): From 1 to 0
    1
        Eating (dexamethasone): From 1 to 1
    2
        Eating (dexamethasone): From 2 to 0
    1
        Eating (dexamethasone): From 2 to 1
    2
        Eating (dexamethasone): From 2 to 2
    1
        Eating (dexamethasone): From 3 to 1
    1
        Eating (SoC): From 1 to 0
    2
        Eating (SoC): From 1 to 1
    1
        Eating (SoC): From 2 to 0
    1
        Eating (SoC): From 3 to 0
    1
        Eating (SoC): From 3 to 1
    2
        Eating (SoC): From 3 to 2
    3
        Eating (SoC): From 4 to 1
    1
        Eating (SoC): From missing value to missing value
    2
        Talking (dexamethasone): From 0 to 0
    6
        Talking (dexamethasone): From 1 to 0
    1
        Talking (dexamethasone): From 2 to 0
    2
        Talking (dexamethasone): From 2 to 1
    1
        Talking (dexamethasone): From 2 to 2
    1
        Talking (SoC): From 0 to 0
    5
        Talking (SoC): From 0 to 1
    1
        Talking (SoC): From 1 to 0
    1
        Talking (SoC): From 2 to 0
    1
        Talking (SoC): From 2 to 1
    1
        Talking (SoC): From 3 to 0
    1
        Talking (SoC): From 3 to 2
    1
        Talking (SoC): From missing value to missing value
    2
        Sleeping (dexamethasone): From 0 to 0
    7
        Sleeping (dexamethasone): From 1 to 0
    1
        Sleeping (dexamethasone): From 2 to 0
    1
        Sleeping (dexamethasone): From 2 to 1
    1
        Sleeping (dexamethasone): From 2 to 2
    1
        Sleeping (SoC): From 0 to 0
    5
        Sleeping (SoC): From 0 to 2
    1
        Sleeping (SoC): From 1 to 1
    1
        Sleeping (SoC): From 2 to 0
    2
        Sleeping (SoC): From 3 to 0
    1
        Sleeping (SoC): From 3 to 1
    1
        Sleeping(SoC):From missing value to missing value
    2
    No statistical analyses for this end point

    Secondary: First-line treatment (stomatitis sub-study): Number of participants with shift of response in OSDQ score on mouth pain severity at the end of the first stomatitis episode

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    End point title
    		 First-line treatment (stomatitis sub-study): Number of participants with shift of response in OSDQ score on mouth pain severity at the end of the first stomatitis episode
    End point description
    The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The fifth item asked the participant to rate their mouth pain severity from 0 (no pain) to 10 (unbearable pain). The mouth pain severity OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment. Only participants who were randomized in the stomatitis sub-study were included in this analysis.
    End point type
    Secondary
    End point timeframe
    From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
    End point values
    		 Everolimus+letrozole (first-line treatment)
    Number of subjects analysed
    24
    Units: Participants
        Dexamethasone: From 0 to 0
    1
        Dexamethasone: From 1 to 2
    1
        Dexamethasone: From 2 to 0
    2
        Dexamethasone: From 3 to 0
    2
        Dexamethasone: From 3 to 1
    1
        Dexamethasone: From 3 to 2
    1
        Dexamethasone: From 5 to 2
    1
        Dexamethasone: From 5 to 3
    1
        Dexamethasone: From 7 to 1
    1
        SoC: From 1 to 0
    1
        SoC: From 1 to 1
    1
        SoC: From 4 to 1
    2
        SoC: From 5 to 5
    1
        SoC: From 7 to 0
    1
        SoC: From 8 to 2
    1
        SoC: From 8 to 4
    2
        SoC: From 8 to 6
    1
        SoC: From 9 to 0
    1
        SoC: From missing value to missing value
    2
    No statistical analyses for this end point

    Secondary: First-line treatment (stomatitis sub-study): Number of participants with shift of response in OSDQ score on mouth pain severity affecting daily activities at the end of the first stomatitis episode

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    End point title
    		 First-line treatment (stomatitis sub-study): Number of participants with shift of response in OSDQ score on mouth pain severity affecting daily activities at the end of the first stomatitis episode
    End point description
    The OSDQ is a patient self-administered 6-item questionnaire with a 24-hour recall period. Participants completed the questionnaire daily until the resolution of the stomatitis episode. The sixth item asked the participant to rate their mouth pain severity affecting daily activities score from 0 (no effect on daily activities) to 10 (completely prevented from doing daily activities). The mouth pain severity affecting daily activities OSDQ scores are presented as the shift from Day 1 of first stomatitis episode value to the value at the end of the first episode of stomatitis. Day 1 is defined as the first OSDQ questionnaire recorded. End of first stomatitis value is defined as the last OSDQ questionnaire of the first episode of stomatitis. PROs were assessed up to 24 months after last patient's recruitment. Only participants who were randomized in the stomatitis sub-study were included in this analysis.
    End point type
    Secondary
    End point timeframe
    From start date of first stomatitis episode until its resolution, assessed up to 3.8 years
    End point values
    		 Everolimus+letrozole (first-line treatment)
    Number of subjects analysed
    24
    Units: Participants
        Dexamethasone: From 0 to 0
    5
        Dexamethasone: From 1 to 0
    1
        Dexamethasone: From 2 to 0
    2
        Dexamethasone: From 3 to 2
    1
        Dexamethasone: From 5 to 3
    1
        Dexamethasone: From 6 to 1
    1
        SoC: From 0 to 0
    4
        SoC: From 1 to 4
    1
        SoC: From 2 to 2
    1
        SoC: From 3 to 0
    1
        SoC: From 3 to 1
    1
        SoC: From 5 to 2
    1
        SoC: From 5 to 5
    1
        SoC: From 9 to 0
    1
        SoC: From missing value to missing value
    2
    No statistical analyses for this end point

    Secondary: Number of participants with clinical benfit during extension phase

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    End point title
    		 Number of participants with clinical benfit during extension phase
    End point description
    Number of participants with clinical benefit as judged by the investigator during the extension phase. The extension phase for up to 3 years for participants who were continuing to benefit from study treatment following the end of the core study phase (24 months after last patient's recruitment) was added in the amendment 5 (dated 14-Feb-2017). Results are presented by line of treatment
    End point type
    Secondary
    End point timeframe
    From the end of core phase (upon approval of amendment 5) up to approximately 3 years
    End point values
    		 Everolimus+letrozole (first-line treatment) Everolimus+exemestane (second-line treatment)
    Number of subjects analysed
    202
    53
    Units: Participants
        Extension Week 1
    34
    6
        Extension Week 12
    30
    5
        Extension Week 24
    28
    4
        Extension Week 36
    23
    3
        Extension Week 48
    20
    3
        Extension Week 60
    18
    3
        Extension Week 72
    16
    3
        Extension Week 84
    13
    3
        Extension Week 96
    12
    3
        Extension Week 108
    12
    3
        Extension Week 120
    11
    2
        Extension Week 132
    10
    1
        Extension Week 144
    8
    1
        Extension End of treatment
    11
    1
    No statistical analyses for this end point

    Post-hoc: All collected deaths

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    End point title
    		 All collected deaths
    End point description
    On-treatment deaths in first line were collected from first dose of first-line treatment until the date of last administration of the first-line study treatment plus 28 days for participants not entering second-line or the minimum between the date of last administration of the first-line study treatment plus 28 days and the date of first administration of second-line study treatment minus one day for participants entering second line, up to 7.3 years. On-treatment deaths in second line were collected from first dose of second-line treatment to 28 days after the last administration of second-line treatment, up to 5.4 years. Post-treatment deaths were collected from day 29 after last dose of study treatment to end of study, up to 7.3 years. All deaths refer to the sum of on-treatment deaths and post-treatment deaths.
    End point type
    Post-hoc
    End point timeframe
    On-treatment deaths (first line): Up to 7.3 years. On-treatment deaths (second line): Up to 5.4 years. Post-treatment and all deaths: Up to 7.3 years
    End point values
    		 Everolimus+letrozole/exemestane
    Number of subjects analysed
    202
    Units: Participants
        On -treatment deaths in first line
    11
        On-treatment deaths in second line
    2
        Post-treatment deaths
    49
        All deaths
    62
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First line: from first dose of first-line treatment up to 7.3 years Second line: from first dose of second-line treatment up to 5.4 years
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Everolimus + Exemestane
    Reporting group description
    		 Participants who had disease progression in the first line setting (core phase) were treated with second-line treatment (everolimus in combination with exemestane)

    Reporting group title
    Everolimus + Letrozole
    Reporting group description
    		 Participants received everolimus in combination with letrozole as first-line treatment.

    Serious adverse events
    		 Everolimus + Exemestane Everolimus + Letrozole
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 53 (15.09%)
    72 / 202 (35.64%)
         number of deaths (all causes)
    2
    11
         number of deaths resulting from adverse events
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         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
    Urogenital prolapse
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         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
    Acute respiratory failure
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 53 (1.89%)
    6 / 202 (2.97%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchostenosis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 53 (1.89%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Snake bite
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 53 (0.00%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bicytopenia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    5 / 202 (2.48%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pupils unequal
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral hernia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 53 (0.00%)
    5 / 202 (2.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 53 (0.00%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocyturia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 53 (0.00%)
    5 / 202 (2.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         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 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 53 (0.00%)
    4 / 202 (1.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis viral
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 53 (1.89%)
    9 / 202 (4.46%)
         occurrences causally related to treatment / all
    0 / 1
    5 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia bacterial
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         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 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Soft tissue infection
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Everolimus + Exemestane Everolimus + Letrozole
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 53 (86.79%)
    202 / 202 (100.00%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    7 / 53 (13.21%)
    21 / 202 (10.40%)
         occurrences all number
    10
    52
    Blood creatinine increased
         subjects affected / exposed
    3 / 53 (5.66%)
    18 / 202 (8.91%)
         occurrences all number
    7
    31
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 53 (9.43%)
    36 / 202 (17.82%)
         occurrences all number
    5
    48
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 53 (9.43%)
    42 / 202 (20.79%)
         occurrences all number
    6
    58
    Blood cholesterol increased
         subjects affected / exposed
    0 / 53 (0.00%)
    42 / 202 (20.79%)
         occurrences all number
    0
    71
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 53 (5.66%)
    5 / 202 (2.48%)
         occurrences all number
    3
    5
    Weight decreased
         subjects affected / exposed
    15 / 53 (28.30%)
    91 / 202 (45.05%)
         occurrences all number
    18
    104
    White blood cell count decreased
         subjects affected / exposed
    3 / 53 (5.66%)
    9 / 202 (4.46%)
         occurrences all number
    5
    26
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 53 (1.89%)
    15 / 202 (7.43%)
         occurrences all number
    1
    19
    Hypertension
         subjects affected / exposed
    9 / 53 (16.98%)
    50 / 202 (24.75%)
         occurrences all number
    13
    66
    Lymphoedema
         subjects affected / exposed
    1 / 53 (1.89%)
    18 / 202 (8.91%)
         occurrences all number
    1
    19
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 53 (7.55%)
    34 / 202 (16.83%)
         occurrences all number
    5
    55
    Dysgeusia
         subjects affected / exposed
    1 / 53 (1.89%)
    32 / 202 (15.84%)
         occurrences all number
    1
    33
    Dizziness
         subjects affected / exposed
    1 / 53 (1.89%)
    19 / 202 (9.41%)
         occurrences all number
    1
    26
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 53 (1.89%)
    15 / 202 (7.43%)
         occurrences all number
    1
    28
    Anaemia
         subjects affected / exposed
    11 / 53 (20.75%)
    71 / 202 (35.15%)
         occurrences all number
    13
    158
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 53 (5.66%)
    37 / 202 (18.32%)
         occurrences all number
    6
    50
    Oedema peripheral
         subjects affected / exposed
    6 / 53 (11.32%)
    63 / 202 (31.19%)
         occurrences all number
    7
    104
    Influenza like illness
         subjects affected / exposed
    3 / 53 (5.66%)
    7 / 202 (3.47%)
         occurrences all number
    3
    10
    Fatigue
         subjects affected / exposed
    5 / 53 (9.43%)
    70 / 202 (34.65%)
         occurrences all number
    5
    96
    Asthenia
         subjects affected / exposed
    2 / 53 (3.77%)
    32 / 202 (15.84%)
         occurrences all number
    3
    46
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 53 (7.55%)
    21 / 202 (10.40%)
         occurrences all number
    4
    23
    Abdominal pain upper
         subjects affected / exposed
    1 / 53 (1.89%)
    15 / 202 (7.43%)
         occurrences all number
    1
    18
    Constipation
         subjects affected / exposed
    1 / 53 (1.89%)
    34 / 202 (16.83%)
         occurrences all number
    1
    44
    Diarrhoea
         subjects affected / exposed
    2 / 53 (3.77%)
    81 / 202 (40.10%)
         occurrences all number
    2
    124
    Dry mouth
         subjects affected / exposed
    0 / 53 (0.00%)
    12 / 202 (5.94%)
         occurrences all number
    0
    12
    Nausea
         subjects affected / exposed
    4 / 53 (7.55%)
    73 / 202 (36.14%)
         occurrences all number
    6
    116
    Toothache
         subjects affected / exposed
    2 / 53 (3.77%)
    13 / 202 (6.44%)
         occurrences all number
    2
    14
    Stomatitis
         subjects affected / exposed
    10 / 53 (18.87%)
    139 / 202 (68.81%)
         occurrences all number
    30
    370
    Oral pain
         subjects affected / exposed
    1 / 53 (1.89%)
    12 / 202 (5.94%)
         occurrences all number
    1
    13
    Vomiting
         subjects affected / exposed
    7 / 53 (13.21%)
    31 / 202 (15.35%)
         occurrences all number
    7
    41
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 53 (5.66%)
    48 / 202 (23.76%)
         occurrences all number
    3
    64
    Cough
         subjects affected / exposed
    7 / 53 (13.21%)
    70 / 202 (34.65%)
         occurrences all number
    7
    113
    Epistaxis
         subjects affected / exposed
    1 / 53 (1.89%)
    36 / 202 (17.82%)
         occurrences all number
    2
    50
    Interstitial lung disease
         subjects affected / exposed
    1 / 53 (1.89%)
    15 / 202 (7.43%)
         occurrences all number
    1
    17
    Nasal congestion
         subjects affected / exposed
    0 / 53 (0.00%)
    12 / 202 (5.94%)
         occurrences all number
    0
    16
    Pneumonitis
         subjects affected / exposed
    2 / 53 (3.77%)
    36 / 202 (17.82%)
         occurrences all number
    2
    40
    Pleural effusion
         subjects affected / exposed
    0 / 53 (0.00%)
    14 / 202 (6.93%)
         occurrences all number
    0
    17
    Oropharyngeal pain
         subjects affected / exposed
    1 / 53 (1.89%)
    12 / 202 (5.94%)
         occurrences all number
    1
    16
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 53 (3.77%)
    12 / 202 (5.94%)
         occurrences all number
    2
    12
    Dermatitis acneiform
         subjects affected / exposed
    3 / 53 (5.66%)
    4 / 202 (1.98%)
         occurrences all number
    6
    5
    Dry skin
         subjects affected / exposed
    1 / 53 (1.89%)
    24 / 202 (11.88%)
         occurrences all number
    1
    28
    Erythema
         subjects affected / exposed
    0 / 53 (0.00%)
    15 / 202 (7.43%)
         occurrences all number
    0
    17
    Nail disorder
         subjects affected / exposed
    0 / 53 (0.00%)
    12 / 202 (5.94%)
         occurrences all number
    0
    13
    Pruritus
         subjects affected / exposed
    1 / 53 (1.89%)
    35 / 202 (17.33%)
         occurrences all number
    1
    40
    Rash
         subjects affected / exposed
    0 / 53 (0.00%)
    56 / 202 (27.72%)
         occurrences all number
    0
    84
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 53 (0.00%)
    16 / 202 (7.92%)
         occurrences all number
    0
    19
    Insomnia
         subjects affected / exposed
    3 / 53 (5.66%)
    20 / 202 (9.90%)
         occurrences all number
    3
    22
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 53 (13.21%)
    59 / 202 (29.21%)
         occurrences all number
    7
    92
    Back pain
         subjects affected / exposed
    3 / 53 (5.66%)
    30 / 202 (14.85%)
         occurrences all number
    4
    34
    Pain in extremity
         subjects affected / exposed
    2 / 53 (3.77%)
    27 / 202 (13.37%)
         occurrences all number
    2
    36
    Myalgia
         subjects affected / exposed
    4 / 53 (7.55%)
    16 / 202 (7.92%)
         occurrences all number
    4
    18
    Bone pain
         subjects affected / exposed
    1 / 53 (1.89%)
    13 / 202 (6.44%)
         occurrences all number
    1
    15
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 53 (3.77%)
    27 / 202 (13.37%)
         occurrences all number
    2
    27
    Nasopharyngitis
         subjects affected / exposed
    6 / 53 (11.32%)
    29 / 202 (14.36%)
         occurrences all number
    15
    53
    Gastroenteritis
         subjects affected / exposed
    1 / 53 (1.89%)
    11 / 202 (5.45%)
         occurrences all number
    3
    11
    Conjunctivitis
         subjects affected / exposed
    1 / 53 (1.89%)
    12 / 202 (5.94%)
         occurrences all number
    1
    16
    Sinusitis
         subjects affected / exposed
    1 / 53 (1.89%)
    14 / 202 (6.93%)
         occurrences all number
    1
    17
    Bronchitis
         subjects affected / exposed
    4 / 53 (7.55%)
    12 / 202 (5.94%)
         occurrences all number
    4
    13
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 53 (7.55%)
    33 / 202 (16.34%)
         occurrences all number
    9
    46
    Urinary tract infection
         subjects affected / exposed
    6 / 53 (11.32%)
    31 / 202 (15.35%)
         occurrences all number
    6
    43
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 53 (9.43%)
    64 / 202 (31.68%)
         occurrences all number
    7
    74
    Hypercalcaemia
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 202 (0.50%)
         occurrences all number
    3
    2
    Hypercholesterolaemia
         subjects affected / exposed
    7 / 53 (13.21%)
    54 / 202 (26.73%)
         occurrences all number
    6
    71
    Hypophosphataemia
         subjects affected / exposed
    1 / 53 (1.89%)
    14 / 202 (6.93%)
         occurrences all number
    1
    27
    Hypokalaemia
         subjects affected / exposed
    2 / 53 (3.77%)
    32 / 202 (15.84%)
         occurrences all number
    2
    53
    Hypertriglyceridaemia
         subjects affected / exposed
    5 / 53 (9.43%)
    72 / 202 (35.64%)
         occurrences all number
    5
    118
    Hyperlipidaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    17 / 202 (8.42%)
         occurrences all number
    0
    18
    Hyperglycaemia
         subjects affected / exposed
    7 / 53 (13.21%)
    59 / 202 (29.21%)
         occurrences all number
    12
    92

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2012
    The purpose of the amendment was to correct the dosage strength of the oral dexamethasone mouth rinse to be administered in the stomatitis therapeutic intervention; to add that patients who discontinued study treatment for any reason other than disease progression or consent withdrawal continued to have tumor assessments until disease progression or until new anticancer therapy was initiated; to add that the ratio for randomization in the stomatitis therapeutic intervention was 1:1 and to remove progesterone receptor from the population description. No patient was enrolled into the study until this amendment
    28 May 2013
    The main purpose of the amendment was to clarify that the dexamethasone therapeutic investigation was only conducted in countries where an alcohol-free 0.5 mg/5 ml dexamethasone solution was commercially available. The availability of alcohol-free dexamethasone solution at the dosage specified in the protocol was geographically limited and this clarification allowed all countries to participate in the study to investigate the activity of everolimus in combination with letrozole in first line and in combination with exemestane in second line even though they cannot participate in the stomatitis assessment part.
    17 Mar 2014
    The main purpose of the amendment was to describe the process for implementing a centralized key eligibility check prior to enrollment of patients to the study. The management of data from OSDQs was also been clarified since the data from the questionnaires were not being entered in a separate electronic database by a designated CRO. Indeed, the data from the OSDQ were entered in the study database by the investigational staff. In addition, the calculation of the clinical benefit rate was clarified to mention that patients with non-measurable disease only at Baseline were included into the numerator of CBR, if they achieved a complete response or stable disease lasting 24 weeks or longer. The wording used to describe the censoring rule for PFS was also clarified. These changes were only to add clarity and did not impact the statistical analysis
    10 Aug 2015
    The main purpose of the amendment was to clarify that patients who were benefiting from treatment with everolimus at the time of overall survival analysis could discontinue this study and transition to commercial everolimus or to a rollover study. The study closure would occur once the last patient last visit in the study had been documented. In addition, the amendment clarified the timing of the analysis of PFS for second-line treatment. This analysis will be performed 18 months after last patient first visit (LPFV) only if there is an adequate number of patients in second-line treatment at that time. Otherwise, the analysis will be performed 24 months after LPFV at the same time as the overall survival analysis.
    14 Feb 2017
    The main purpose of the amendment was to add an Extension Phase for up to three years to continue to monitor safety and provide access to treatment for patients who are continuing to benefit from treatment with everolimus following the overall survival cutoff which is 24 months post last patient first visit (LPFV) of the core study phase. The first line combination treatment (everolimus + letrozole) is not approved in label for any country and for the second line combination (everolimus + exemestane) some countries mandate that the treatment be provided without cost to patients and some countries have limited availability of supply. For these reasons, treatment was continued to be provided to patients receiving treatment at the time of implementation of this amendment. Treatment was provided for the respective line of treatment (first or second) that the patients are currently receiving at the time of starting the Extension Phase. During the Extension Phase, patients were evaluated as per institution’s standard of care to determine clinical benefit and safety was monitored as per the protocol requirements. The purpose of the extension was to continue safety monitoring and provide access to treatment; the only efficacy assessment to be collected was the physician’s determination of whether or not the patient was continuing to clinically benefit from the study treatment

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    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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