Open-label, Phase II, Study of Everolimus Plus Letrozole in Postmenopausal Women With ER+, HER2- Metastatic or Locally Advanced Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study was to assess the efficacy and safety of first-line treatment with everolimus plus letrozole in postmenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer. Moreover, the study also aimed to investigate the efficacy and safety of second line treatment with everolumus plus examestane in participants whose disease progressed during everolimus plus letrozole therapy.

Detailed Description
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This was an open-label, phase II, multicenter, international, single-arm study for postmenopausal women with ER+/HER2- metastatic or locally advanced breast cancer. This study was comprised of 2 phases: - Core Phase: from first participant first visit to 24 months after enrollment of the last participant (and upon approval of amendment 5 dated 14-Feb-2017), up to approximately 4 years. The main purpose of the amendment 5 was to implement an Extension Phase up to 3 years. During the core phase, all enrolled participants received everolimus in combination with letrozole in the first line setting until disease progression or any other reason for which the participant might be discontinued. Only those participants who had disease progression in the first line setting were offered second line treatment (everolimus in combination with exemestane). Participants who discontinued first line treatment due to reasons other than disease progression were not eligible for second line treatment. The participants who were treated in the second line setting continued treatment until disease progression, unacceptable toxicity or withdrawal of consent. - Extension Phase: Participants that were still benefiting from everolimus at the end of the Core Phase (and upon approval of amendment 5 dated 14-Feb-2017) were transitioned to the Extension phase of the study. Participants were continued on their existing line of treatment (everolimus plus letrozole or everolimus plus exemestane) in the extension, up to 3 years or until progression or any other reason for which the participant might be discontinued. Participants entering the Extension Phase on first line treatment and deemed to no longer be clinically benefiting were not offered second line treatment in the context of the study This study included a randomized, open-label sub-study for participants in countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution was commercially available who experienced a stomatitis event: at the first onset of symptoms suggestive of stomatitis, participants were to contact the study site and based on preliminary confirmation of diagnosis, participants were asked to visit the study site within 24 hours. Upon confirmation of stomatitis, participants in countries where the alcohol-free 0.5 mg/5 mL dexamethasone oral solution was commercially available (US sites only) were randomly assigned in a 1:1 ratio to take either 0.5 mg/5 mL dexamethasone mouth rinse or the standard of care used to treat stomatitis at the participant's center. All participants who experienced stomatitis (regardless of inclusion in the sub-study) were instructed to fill out the Oral Stomatitis Daily Questionnaire (OSDQ) at home every day until the participant recovered. For subsequent episodes of stomatitis, participants were instructed to contact the physician. If part of the randomized set upon telephone confirmation, they were instructed to utilize the same treatment they were assigned to after the first episode and complete the OSDQ booklet.

Official Title
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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

Conditions
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Hormone Receptor Positive Breast Cancer

Intervention / Treatment
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* Drug: Everolimus
* Drug: Letrozole
* Drug: Exemestane
* Drug: Alcohol-free dexamethasone mouth rinse (Stomatitis sub-study)
* Drug: Standard of care to treat stomatitis (Stomatitis sub-study)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with metastatic or locally advanced, unresectable breast cancer not amenable to curative treatment by surgery or radiotherapy Histological or cytological confirmation of ER+/ HER2- breast cancer Postmenopausal women No prior treatment for metastatic breast cancer Exclusion Criteria: Patients with only non-measurable lesions other than bone metastases (e.g., pleural effusion, ascites, etc) Patients who had received prior hormonal or any other systemic therapy for metastatic breast cancer. Patients might have received prior neoadjuvant or adjuvant endocrine therapy. In the case of neoadjuvant or adjuvant NSAI (letrozole/anastrozole) therapy patients must have completed therapy at least 1 year prior to study enrollment. Previous treatment with mTOR inhibitors. Known hypersensitivity to mTOR inhibitors, e.g., sirolimus (rapamycin). Other protocol-defined inclusion/exclusion criteria might apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: The main study was an open-label single-arm study. The stomatitis sub-study was a randomized open-label study with two arms: dexamethasone and standard of care.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus+letrozole/exemestane (first line and second line treatment)<br>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) | Drug: Everolimus<br>* 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.<br>* Other names: RAD001;Drug: Letrozole<br>* 1st line study treatment: 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<br>* Other names: Femara;Drug: Exemestane<br>* 2nd Line Study Treatment: 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<br>* Other names: Aromasin;Drug: Alcohol-free dexamethasone mouth rinse (Stomatitis sub-study)<br>* Alcohol-free 0.5mg/5ml dexamethasone oral solution was self-administered at a daily dose of 10ml 3 times per day (participants with confirmed stomatitis who entered the stomatitis sub-study).<br>Drug: Standard of care to treat stomatitis (Stomatitis sub-study)<br>* Standard of care used to treat stomatitis at the patient's center (participants with confirmed stomatitis who entered the stomatitis sub-study).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First-line Treatment: Progression-free Survival (PFS) | 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. | From the date of enrollment to the date of first documented progression or deaths, assessed up to approximately 2.8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First-line Treatment: Overall Response Rate (ORR) | 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. | From the date of enrollment until discontinuation of first-line treatment, assessed up to approximately 3.8 years | 
| First-line Treatment: Clinical Benefit Rate (CBR) | 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 | From the date of enrollment until first-line treatment discontinuation, assessed up to approximately 3.8 years | 
| Second-line Treatment: Progression-free Survival (PFS) | 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. | From the start of the second-line treatment until the date of first documented progression or death, assessed up to approximately 2.4 years | 
| Second-line Treatment: Overall Response Rate (ORR) | 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 | From the start of the second-line treatment up to approximately 2.4 years | 
| Second-line Treatment: Clinical Benefit Rate (CBR) | 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 | From the start of the second-line treatment up to approximately 2.4 years | 
| Overall Survival (OS) | 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. | From the date of enrollment to date of death, assessed up to approximately 3.8 years | 
| First-line Treatment: Time to First Stomatitis Episode as Assessed by the Oral Stomatitis Daily Questionnaire (OSDQ) | 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. | From first-line treatment administration until first stomatitis episode in the first line, assessed up to approximately 3.8 years | 
| First-line Treatment: Duration of First Stomatitis Based on OSDQ | 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. | From start date of first stomatitis episode in first line until its resolution, assessed up to 3.8 years | 
| First-line Treatment: Number of Participants With Shift of Response in OSDQ Score on Overall Health at the End of the First Stomatitis Episode | 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. | From start date of first stomatitis episode until its resolution, assessed up to 3.8 years | 
| 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 | 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. | From start date of first stomatitis episode until its resolution, assessed up to 3.8 years | 
| 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 | 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. | From start date of first stomatitis episode until its resolution, assessed up to 3.8 years | 
| 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 | 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. | From start date of first stomatitis episode until its resolution, assessed up to 3.8 years | 
| 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 | 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. | From start date of first stomatitis episode until its resolution, assessed up to 3.8 years | 
| First-line Treatment (Stomatitis Sub-study): Time to First Stomatitis Episode as Assessed by the OSDQ | 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. | From first study treatment administration in the first line until first stomatitis episode, assessed up to approximately 3.8 years | 
| First-line Treatment (Stomatitis Sub-study): Duration of First Stomatitis Based on OSDQ | 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. | From start date of first stomatitis episode until its resolution, assessed up to 3.8 years | 
| 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 | 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. | From start date of first stomatitis episode until its resolution, assessed up to 3.8 years | 
| 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 | 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. | From start date of stomatitis episode until its resolution, assessed up to 3.8 years | 
| 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 | 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. | From start date of first stomatitis episode until its resolution, assessed up to 3.8 years | 
| 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 | 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. | From start date of first stomatitis episode until its resolution, assessed up to 3.8 years | 
| 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 | 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. | From start date of first stomatitis episode until its resolution, assessed up to 3.8 years | 
| Number of Participants With Clinical Benfit During Extension Phase | 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 | From the end of core phase (upon approval of amendment 5) up to approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic breast cancer, Locally advanced breast cancer, HER2-, ER+, Everolimus, Afinitor