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

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.

Time frame: From the date of enrollment to the date of first documented progression or deaths, assessed up to approximately 2.8 years

Population: Full Analysis Set (FAS): All participants to whom the first-line study treatment was assigned

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

Time frame: From the date of enrollment until first-line treatment discontinuation, assessed up to approximately 3.8 years

Population: FAS: All participants to whom the first-line study treatment was assigned

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.

Time frame: From start date of first stomatitis episode in first line until its resolution, assessed up to 3.8 years

Population: First-line stomatitis analysis set (SAS-1L): All participants in the FAS who agreed to fill in the OSDQ and who developed their first stomatitis event (based on 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 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.

Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years

Population: First-line stomatitis analysis set (SAS-1L): All participants in the FAS who agreed to fill in the OSDQ and who developed their first stomatitis event (based on 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 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.

Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years

Population: First-line stomatitis analysis set (SAS-1L): All participants in the FAS who agreed to fill in the OSDQ and who developed their first stomatitis event (based on 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 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.

Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years

Population: First-line stomatitis analysis set (SAS-1L): All participants in the FAS who agreed to fill in the OSDQ and who developed their first stomatitis event (based on 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 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.

Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years

Population: First-line stomatitis analysis set (SAS-1L): All participants in the FAS who agreed to fill in the OSDQ and who developed their first stomatitis event (based on 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 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.

Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years

Population: First-line stomatitis analysis set (SAS-1L): All participants in the FAS who agreed to fill in the OSDQ and who developed their first stomatitis event (based on OSDQ) in the first line.

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.

Time frame: From the date of enrollment until discontinuation of first-line treatment, assessed up to approximately 3.8 years

Population: FAS: All participants to whom the first-line study treatment was assigned

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.

Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years

Population: Stomatitis randomized set: All participants in the FAS who were randomized in the stomatitis sub-study to receive dexamethasone or standard of care (i.e. participants in countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution was commercially available who experienced a stomatitis event). Number analyzed indicates the number of participants randomized to each intervention

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.

Time frame: From start date of stomatitis episode until its resolution, assessed up to 3.8 years

Population: Stomatitis randomized set: All participants in the FAS who were randomized in the stomatitis sub-study to receive dexamethasone or standard of care (i.e. participants in countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution was commercially available who experienced a stomatitis event). Number analyzed indicates the number of participants randomized to each intervention.

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.

Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years

Population: Stomatitis randomized set: All participants in the FAS who were randomized in the stomatitis sub-study to receive dexamethasone or standard of care (i.e. participants in countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution was commercially available who experienced a stomatitis event). Number analyzed indicates the number of participants randomized to each intervention

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.

Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years

Population: Stomatitis randomized set: All participants in the FAS who were randomized in the stomatitis sub-study to receive dexamethasone or standard of care (i.e. participants in countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution was commercially available who experienced a stomatitis event). Number analyzed indicates the number of participants randomized to each intervention

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.

Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years

Population: Stomatitis randomized set: All participants in the FAS who were randomized in the stomatitis sub-study to receive dexamethasone or standard of care (i.e. participants in countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution was commercially available who experienced a stomatitis event). Number analyzed indicates the number of participants randomized to each intervention

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.

Time frame: From start date of first stomatitis episode until its resolution, assessed up to 3.8 years

Population: Stomatitis randomized set: All participants in the FAS who were randomized in the stomatitis sub-study to receive dexamethasone or standard of care (i.e. participants in countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution was commercially available who experienced a stomatitis event). Number analyzed indicates the number of participants randomized to each intervention

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.

Time frame: From first study treatment administration in the first line until first stomatitis episode, assessed up to approximately 3.8 years

Population: Stomatitis randomized set: All participants in the FAS who were randomized in the stomatitis sub-study to receive dexamethasone or standard of care (i.e. participants in countries where the alcohol-free 0.5mg/5ml dexamethasone oral solution was commercially available who experienced a stomatitis event). Number analyzed indicates the number of participants randomized to each intervention

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.

Time frame: From first-line treatment administration until first stomatitis episode in the first line, assessed up to approximately 3.8 years

Population: First-line stomatitis analysis set (SAS-1L): All participants in the FAS who agreed to fill in the OSDQ and who developed their first stomatitis event (based on OSDQ) in the first line.

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

Time frame: From the end of core phase (upon approval of amendment 5) up to approximately 3 years

Population: For first-line treatment, all participants to whom the first-line treatment was assigned (FAS) For second-line treatment, all participants in the FAS who received at least one dose of second-line study medication (FAS-2L)

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.

Time frame: From the date of enrollment to date of death, assessed up to approximately 3.8 years

Population: FAS: All participants to whom the first-line study treatment was assigned

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

Time frame: From the start of the second-line treatment up to approximately 2.4 years

Population: Participants in the FAS-2L, including all participants in the FAS who received at least one dose of second-line study medication, with evaluable data for this endpoint

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

Time frame: From the start of the second-line treatment up to approximately 2.4 years

Population: Participants in the FAS-2L, including all participants in the FAS who received at least one dose of second-line study medication, with evaluable data for this endpoint

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.

Time frame: From the start of the second-line treatment until the date of first documented progression or death, assessed up to approximately 2.4 years

Population: Participants in the Full Analysis Set second line (FAS-2L), including all participants in the FAS who received at least one dose of second-line study medication, with evaluable data for this endpoint.

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 survival follow-up 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.

Time frame: On-treatment deaths in first line: Up to 7.3 years. On-treatment deaths in second line: Up to 5.4 years. Post-treatment and all deaths: Up to 7.3 years

Population: All participants who received at least one dose of study medication and had at least one post-baseline safety assessment. The safety analysis for the second line was performed on the subset of participants receiving at least one dose of second-line medication.