Advanced Breast Cancer
Conditions
Keywords
everolimus, exemestane, advanced Breast Cancer, non-steroidal aromatase inhibitors, breast carcinoma, breast cancer, breast lump, HER2 negative, breast cancer progression
Brief summary
This study aimed at evaluating the safety and efficacy of everolimus plus exemestane in Chinese postmenopausal women with ER+ HER2- locally advanced, recurrent, or metastatic breast cancer after recurrence or progression on letrozole or anastrozole.
Detailed description
This was a multicenter, double-blind, randomized, placebo-controlled, phase II study evaluating treatment with everolimus (10 mg daily) in combination with exemestane (25 mg daily) vs placebo in combination with exemestane (25 mg daily) in Chinese postmenopausal women with locally advanced, recurrent or metastatic ER+ HER2- breast cancer refractory to non-steroidal aromatase inhibitors. Randomized participants started the study treatment at Cycle 1 Day 1, and were treated continuously until disease progression (assessed by RECIST 1.1), unacceptable toxicity, death or discontinuation from treatment for any other reason. After end of treatment, all participants were followed up for safety up to 30 days after last dose of study treatment (exemestane and/or everolimus/placebo). All participants were followed for survival status at least every 3 months after treatment discontinuation unless they discontinued due to death, consent withdrawal or lost to follow-up If a participants permanently discontinued study treatment for reasons other than disease progression, death, lost to follow-up, or withdrawal of consent to efficacy follow-up then they entered the post-treatment efficacy follow-up period until disease progression, death, lost to follow-up or withdrawal of consent for efficacy follow-up.
Interventions
DRUGEverolimus
Everolimus was formulated as tablets of 5 mg strength and was packaged into blister packs . Everolimus (two 5 mg tablets daily) was administered in a blinded manner by continuous oral daily dosing.
DRUGExemestane
Commercially available exemestane was supplied as 25 mg tablets. Exemestane was administered as continuous oral daily dose of 25 mg tablets.
Placebo was formulated to be indistinguishable from the everolimus tablets. Matching placebo (two tablets daily) was administered in a blinded manner by continuous oral daily dosing.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Chinese Postmenopausal women with ER+ HER2- locally advanced, recurrent, or metastatic breast cancer. Locally advanced breast cancer must not be amenable to curative treatment by surgery or radiotherapy. * Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer * Postmenopausal women. Postmenopausal status was defined either by: * Prior bilateral oophorectomy * Or age ≥60 * Or age \< 60 and amenorrhea for 12 or more months * Recurrence or progression on prior NSAI was defined as: * Recurrence while on, or within one year (12 months) of end of adjuvant treatment with letrozole or anastrozole * Or Progression while on or within one month (30 days) of the end of prior treatment with letrozole or anastrozole * Radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to enrollment * Patient had as per RECIST 1.1 * measurable disease or non-measurable lytic or mixed (lytic + blastic) bone lesions in the absence of measurable disease. * non-measurable lytic or mixed (lytic + blastic) bone lesions in the absence of measurable disease. * Patient was able to swallow and retain oral medication * Patient met the hematologic and biochemistery laboratory values at the screening visit * Patient had a WHO performance status ≤2 * Written informed consent obtained prior to any screening procedures
Exclusion criteria
* HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive), based on the most recent test. * Patients who had received more than one chemotherapy line for ABC * Patients with symptomatic visceral disease and candidates to chemotherapy * Patients with only non-measurable lesions other than lytic or mixed (lytic and blastic) bone metastasis (e.g. pleural effusion, ascites etc.) * Patients receiving concomitant immunosuppressive agents or chronic corticosteroids used at the time of study entry except topical applications, inhaled sprays, eye drops or local injections. * Uncontrolled diabetes mellitus as defined by HbA1c \>7% despite adequate therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Based on Local Radiology Review of Tumor Assessment | From randomization up to date of first documented progression or death, assessed up to approximately 3.5 years | PFS was defined as time from the date of randomization to the date of first documented progression or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. Disease progression was assessed using the local investigator's tumor assessment per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. The distribution of PFS was estimated using the Kaplan-Meier method. Cox regression model stratified by randomization stratification factors was used to estimate the hazard ratio (HR) of PFS, along with 90% CI. As this was an estimation based approach, no p-value was provided. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization to date of death, up to approximately 3.8 years | OS was defined as the time from date of randomization to date of death due to any cause. If the participant was alive at the date of the analysis cut-off or lost to follow-up, then OS was censored at the last contact date prior to data cutoff date. The distribution of OS was estimated using the Kaplan-Meier method. Cox regression model stratified by randomization stratification factors was used to estimate the hazard ratio (HR) of OS, along with 90% CI. As this was an estimation based approach, no p-value was provided. |
| Overall Response Rate (ORR) Based on Local Radiology Review of Tumor Assessment | Up to approximately 3.5 years | ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR) according to RECIST using local radiologist's/investigator's tumor assessment. ORR was estimated and the exact binomial 90% CI was reported by treatment arm. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Overall Response Rate (ORR) Based on BIRC Assessment | Up to approximately 1.8 years | ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR) according to RECIST using BIRC assessment. ORR was estimated and the exact binomial 90% CI was reported by treatment arm. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Clinical Benefit Rate (CBR) Based on Local Radiology Review of Tumor Assessment | Up to approximately 3.5 years | CBR was defined as the percentage of patients with best overall response of CR, PR or an overall lesion response of stable disease (SD) or Non-CR/Non-progressive disease with duration of 24 weeks or longer according to RECIST 1.1 using local radiologist's/investigator's tumor assessment. CBR was estimated and the exact binomial 90% CI was reported by treatment arm. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease. |
| Clinical Benefit Rate (CBR) Based on BIRC Assessment | Up to approximately 1.8 years | CBR was defined as the percentage of patients with best overall response of CR, PR or an overall lesion response of stable disease (SD) or Non-CR/Non-progressive disease with duration of 24 weeks or longer according to RECIST 1.1 using BIRC assessment. CBR was estimated and the exact binomial 90% CI was reported by treatment arm. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease. |
| Time to Response (TTR) Based on Local Radiology Review of Tumor Assessment | Up to approximately 3.5 years | TTR was defined as the time between date of randomization until first documented response (CR or PR) according to RECIST 1.1 using local radiologist's/investigator's tumor assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Time to Response (TTR) Based on BIRC Assessment | Up to approximately 1.8 years | TTR was defined as the time between date of randomization until first documented response (CR or PR) according to RECIST 1.1 using BIRC assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Progression-free Survival (PFS) Based on Blinded Independent Review Committee (BIRC) Assessment | From randomization up to date of first documented progression or death, assessed up to approximately 1.8 years | PFS was defined as time from the date of randomization to the date of first documented progression or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. Disease progression was assessed using the BIRC tumor assessment per RECIST 1.1. The distribution of PFS was estimated using the Kaplan-Meier method. Cox regression model stratified by randomization stratification factors was used to estimate the hazard ratio (HR) of PFS, along with 90% CI. As this was an estimation based approach, no p-value was provided. |
| Duration of Response (DOR) Based on BIRC Assessment | From date of first documented response to date of first documented disease progression or death, assessed up to approximately 1.8 years | DOR was defined as the time from date of first documented CR or PR to date of first documented disease progression or death due to any cause, according to RECIST 1.1 using BIRC assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Time to Definitive Deterioration of the Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score From Baseline | From randomization up to definitive deterioration of the ECOG PS by one categotu of the score, assessed up to approximately 3.5 years | ECOG PS is a measure of functional status with scores ranging from 0 (fully active) to 5 (dead). Deterioration was considered definitive if no improvements in the ECOG PS status were observed after an instance of deterioration. Death was considered as worsening of the ECOG PS if it occurred close to the last assessment, where close is defined as twice the planned period between two assessments. Participants who died after more than twice the planned period between two assessments were censored at the date of their last assessment before the cut-off. Participants receiving any further anticancer therapy prior to definitive worsening were censored at their date of last assessment prior to start of therapy. Participants that had not worsened were censored at the date of last assessment prior to cut off. Time to definitive deterioration was estimated using the Kaplan-Meier method. |
| Everolimus Predose Concentration (Cmin) | Predose on Cycle 1 Week 4 ( each cycle is defined as 4 weeks) | Blood samples were collected to assess everolimus predose concentration (Cmin) at steady state at Cycle 1 Week 4 (any day during week 4). Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Everolimus concentrations were determined in the whole blood by a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. The method has a lower limit of quantitation (LLOQ) of 0.3 ng/mL for everolimus. Values below the LLOQ were set to 0. |
| Everolimus Concentration at 2 Hours Post Dose (C2h) | Two hours post everolimus administration on Cycle 1 Week 4 ( each cycle is defined as 4 weeks) | Blood samples were collected to assess everolimus concentration at 2 hours post dose (C2h) at steady state at Cycle 1 Week 4 (any day during week 4) Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Everolimus concentrations were determined in the whole blood by a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. The method has a LLOQ of 0.3 ng/mL for everolimus. Values below the LLOQ were set to 0. |
| Exemestane Predose Concentration (Cmin) | Predose of exemestane on Cycle 1 Week 4 ( each cycle is defined as 4 weeks) | Blood samples were collected to assess exemestane predose concentration (Cmin) at steady state at Cycle 1 Week 4 (any day during week 4). Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Exemestane concentrations were determined in the whole blood by a liquid chromatography with LC-MS/MS method. The method has a LLOQ of 20 pg/mL for exemestane. Values below the LLOQ were set to 0. |
| Exemestane Concentration at 2 Hours Post Dose (C2h) | Two hours post exemestane administration on Cycle 1 Week 4 ( each cycle is defined as 4 weeks) | Blood samples were collected to assess exemestane concentration at 2 hours post dose (C2h) at steady state at Cycle 1 Week 4 (any day during week 4) Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Exemestane concentrations were determined in the whole blood by a liquid chromatography with LC-MS/MS method. The method has a LLOQ of 20 pg/mL for exemestane. Values below the LLOQ were set to 0. |
| Estradiol Levels After 4 Weeks of Study Treatment | Baseline, and at Cycle 1 Week 4 prior to any study drug (each cycle is defined as 4 weeks) | Blood samples were collected to assess estradiol levels after 4 weeks of study treatment. Estradiol was determined in plasma using competitive immunoassay. The method has a LLOQ of 1.952 pg/mL for estradiol. Values below the LLOQ were set to 0. |
| Duration of Response (DOR) Based on Local Radiology Review of Tumor Assessment | From date of first documented response to date of first documented disease progression or death, assessed up to approximately 3.5 years | DOR was defined as the time from date of first documented CR or PR to date of first documented disease progression or death due to any cause, according to RECIST 1.1 using local radiologist's/investigator's tumor assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
Countries
China
Participant flow
Recruitment details
Participants took part in 15 investigative sites in China
Pre-assignment details
The screening period began once patients had signed the study informed consent. All screening/baseline evaluations were performed within maximum 21 days prior to the first dose of study treatment
Participants by arm
| Arm | Count |
|---|---|
| Everolimus + Exemestane Participants received everolimus as a continuous oral daily dose of 10 mg and exemestane as a continuous oral daily dose of 25 mg | 80 |
| Placebo + Exemestane Participants received placebo as a continuous oral daily dose and exemestane as a continuous oral daily dose of 25 mg | 79 |
| Total | 159 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 3 |
| Overall Study | Patient/guardian decision | 13 | 5 |
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Progressive disease | 58 | 67 |
| Overall Study | Protocol deviation | 2 | 0 |
| Overall Study | Technical problems | 0 | 1 |
Baseline characteristics
| Characteristic | Everolimus + Exemestane | Placebo + Exemestane | Total |
|---|---|---|---|
| Age, Continuous | 56.6 Years STANDARD_DEVIATION 9.14 | 56.3 Years STANDARD_DEVIATION 8.43 | 56.4 Years STANDARD_DEVIATION 8.77 |
| Race/Ethnicity, Customized Asian | 80 Participants | 79 Participants | 159 Participants |
| Sex: Female, Male Female | 80 Participants | 79 Participants | 159 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 80 | 2 / 79 | 41 / 73 | 43 / 75 |
| other Total, other adverse events | 79 / 80 | 62 / 79 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 18 / 80 | 10 / 79 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Progression-free Survival (PFS) Based on Local Radiology Review of Tumor Assessment
PFS was defined as time from the date of randomization to the date of first documented progression or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. Disease progression was assessed using the local investigator's tumor assessment per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. The distribution of PFS was estimated using the Kaplan-Meier method. Cox regression model stratified by randomization stratification factors was used to estimate the hazard ratio (HR) of PFS, along with 90% CI. As this was an estimation based approach, no p-value was provided.
Time frame: From randomization up to date of first documented progression or death, assessed up to approximately 3.5 years
Population: Full Analysis Set (FAS) including all subjects to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Exemestane | Progression-free Survival (PFS) Based on Local Radiology Review of Tumor Assessment | 7.4 Months |
| Placebo + Exemestane | Progression-free Survival (PFS) Based on Local Radiology Review of Tumor Assessment | 2.0 Months |
90% CI: [0.4, 0.71]
Secondary
Clinical Benefit Rate (CBR) Based on BIRC Assessment
CBR was defined as the percentage of patients with best overall response of CR, PR or an overall lesion response of stable disease (SD) or Non-CR/Non-progressive disease with duration of 24 weeks or longer according to RECIST 1.1 using BIRC assessment. CBR was estimated and the exact binomial 90% CI was reported by treatment arm. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Time frame: Up to approximately 1.8 years
Population: FAS including all subjects to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + Exemestane | Clinical Benefit Rate (CBR) Based on BIRC Assessment | 31.3 Percentage of participants |
| Placebo + Exemestane | Clinical Benefit Rate (CBR) Based on BIRC Assessment | 11.4 Percentage of participants |
Secondary
Clinical Benefit Rate (CBR) Based on Local Radiology Review of Tumor Assessment
CBR was defined as the percentage of patients with best overall response of CR, PR or an overall lesion response of stable disease (SD) or Non-CR/Non-progressive disease with duration of 24 weeks or longer according to RECIST 1.1 using local radiologist's/investigator's tumor assessment. CBR was estimated and the exact binomial 90% CI was reported by treatment arm. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Time frame: Up to approximately 3.5 years
Population: FAS including all subjects to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + Exemestane | Clinical Benefit Rate (CBR) Based on Local Radiology Review of Tumor Assessment | 42.5 Percentage of participants |
| Placebo + Exemestane | Clinical Benefit Rate (CBR) Based on Local Radiology Review of Tumor Assessment | 16.5 Percentage of participants |
Secondary
Duration of Response (DOR) Based on BIRC Assessment
DOR was defined as the time from date of first documented CR or PR to date of first documented disease progression or death due to any cause, according to RECIST 1.1 using BIRC assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: From date of first documented response to date of first documented disease progression or death, assessed up to approximately 1.8 years
Population: Participants in the FAS with a confirmed CR or PR as per BIRC assessment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Exemestane | Duration of Response (DOR) Based on BIRC Assessment | 148.0 Days |
| Placebo + Exemestane | Duration of Response (DOR) Based on BIRC Assessment | 279.0 Days |
Secondary
Duration of Response (DOR) Based on Local Radiology Review of Tumor Assessment
DOR was defined as the time from date of first documented CR or PR to date of first documented disease progression or death due to any cause, according to RECIST 1.1 using local radiologist's/investigator's tumor assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: From date of first documented response to date of first documented disease progression or death, assessed up to approximately 3.5 years
Population: Participants in the FAS with a confirmed CR or PR as per local radiologist's/investigator's tumor assessment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Exemestane | Duration of Response (DOR) Based on Local Radiology Review of Tumor Assessment | 243.5 Days |
| Placebo + Exemestane | Duration of Response (DOR) Based on Local Radiology Review of Tumor Assessment | 561.5 Days |
Secondary
Estradiol Levels After 4 Weeks of Study Treatment
Blood samples were collected to assess estradiol levels after 4 weeks of study treatment. Estradiol was determined in plasma using competitive immunoassay. The method has a LLOQ of 1.952 pg/mL for estradiol. Values below the LLOQ were set to 0.
Time frame: Baseline, and at Cycle 1 Week 4 prior to any study drug (each cycle is defined as 4 weeks)
Population: All subjects with evaluable estradiol concentrations at the specified time points
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus + Exemestane | Estradiol Levels After 4 Weeks of Study Treatment | Baseline | 5.98 pg/mL | Geometric Coefficient of Variation 10.5 |
| Everolimus + Exemestane | Estradiol Levels After 4 Weeks of Study Treatment | Week 4 | 3.98 pg/mL | Geometric Coefficient of Variation 7.77 |
| Placebo + Exemestane | Estradiol Levels After 4 Weeks of Study Treatment | Baseline | 5.38 pg/mL | Geometric Coefficient of Variation 10.4 |
| Placebo + Exemestane | Estradiol Levels After 4 Weeks of Study Treatment | Week 4 | 3.77 pg/mL | Geometric Coefficient of Variation 6.8 |
Secondary
Everolimus Concentration at 2 Hours Post Dose (C2h)
Blood samples were collected to assess everolimus concentration at 2 hours post dose (C2h) at steady state at Cycle 1 Week 4 (any day during week 4) Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Everolimus concentrations were determined in the whole blood by a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. The method has a LLOQ of 0.3 ng/mL for everolimus. Values below the LLOQ were set to 0.
Time frame: Two hours post everolimus administration on Cycle 1 Week 4 ( each cycle is defined as 4 weeks)
Population: All subjects with an evaluable everolimus concentration at the specified time point
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Everolimus + Exemestane | Everolimus Concentration at 2 Hours Post Dose (C2h) | 44.2 ng/mL | Geometric Coefficient of Variation 57.8 |
Secondary
Everolimus Predose Concentration (Cmin)
Blood samples were collected to assess everolimus predose concentration (Cmin) at steady state at Cycle 1 Week 4 (any day during week 4). Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Everolimus concentrations were determined in the whole blood by a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. The method has a lower limit of quantitation (LLOQ) of 0.3 ng/mL for everolimus. Values below the LLOQ were set to 0.
Time frame: Predose on Cycle 1 Week 4 ( each cycle is defined as 4 weeks)
Population: All subjects with an evaluable everolimus concentration at the specified time point
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Everolimus + Exemestane | Everolimus Predose Concentration (Cmin) | 16.5 nanogram/mililiter (ng/mL) | Geometric Coefficient of Variation 59.1 |
Secondary
Exemestane Concentration at 2 Hours Post Dose (C2h)
Blood samples were collected to assess exemestane concentration at 2 hours post dose (C2h) at steady state at Cycle 1 Week 4 (any day during week 4) Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Exemestane concentrations were determined in the whole blood by a liquid chromatography with LC-MS/MS method. The method has a LLOQ of 20 pg/mL for exemestane. Values below the LLOQ were set to 0.
Time frame: Two hours post exemestane administration on Cycle 1 Week 4 ( each cycle is defined as 4 weeks)
Population: All subjects with an evaluable exemestane concentration at the specified time point
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Everolimus + Exemestane | Exemestane Concentration at 2 Hours Post Dose (C2h) | 20500 pg/mL | Geometric Coefficient of Variation 97.1 |
| Placebo + Exemestane | Exemestane Concentration at 2 Hours Post Dose (C2h) | 14300 pg/mL | Geometric Coefficient of Variation 71.6 |
Secondary
Exemestane Predose Concentration (Cmin)
Blood samples were collected to assess exemestane predose concentration (Cmin) at steady state at Cycle 1 Week 4 (any day during week 4). Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Exemestane concentrations were determined in the whole blood by a liquid chromatography with LC-MS/MS method. The method has a LLOQ of 20 pg/mL for exemestane. Values below the LLOQ were set to 0.
Time frame: Predose of exemestane on Cycle 1 Week 4 ( each cycle is defined as 4 weeks)
Population: All subjects with an evaluable exemestane concentration at the specified time point
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Everolimus + Exemestane | Exemestane Predose Concentration (Cmin) | 737 picogram/mililiter (pg/mL) | Geometric Coefficient of Variation 74.2 |
| Placebo + Exemestane | Exemestane Predose Concentration (Cmin) | 502 picogram/mililiter (pg/mL) | Geometric Coefficient of Variation 48.7 |
Secondary
Overall Response Rate (ORR) Based on BIRC Assessment
ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR) according to RECIST using BIRC assessment. ORR was estimated and the exact binomial 90% CI was reported by treatment arm. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 1.8 years
Population: FAS including all subjects to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + Exemestane | Overall Response Rate (ORR) Based on BIRC Assessment | 8.8 Percentage of participants |
| Placebo + Exemestane | Overall Response Rate (ORR) Based on BIRC Assessment | 2.5 Percentage of participants |
Secondary
Overall Response Rate (ORR) Based on Local Radiology Review of Tumor Assessment
ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR) according to RECIST using local radiologist's/investigator's tumor assessment. ORR was estimated and the exact binomial 90% CI was reported by treatment arm. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 3.5 years
Population: FAS including all subjects to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + Exemestane | Overall Response Rate (ORR) Based on Local Radiology Review of Tumor Assessment | 10.0 Percentage of participants |
| Placebo + Exemestane | Overall Response Rate (ORR) Based on Local Radiology Review of Tumor Assessment | 2.5 Percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as the time from date of randomization to date of death due to any cause. If the participant was alive at the date of the analysis cut-off or lost to follow-up, then OS was censored at the last contact date prior to data cutoff date. The distribution of OS was estimated using the Kaplan-Meier method. Cox regression model stratified by randomization stratification factors was used to estimate the hazard ratio (HR) of OS, along with 90% CI. As this was an estimation based approach, no p-value was provided.
Time frame: From randomization to date of death, up to approximately 3.8 years
Population: FAS including all subjects to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Exemestane | Overall Survival (OS) | 26.1 Months |
| Placebo + Exemestane | Overall Survival (OS) | 22.7 Months |
90% CI: [0.69, 1.89]
Secondary
Progression-free Survival (PFS) Based on Blinded Independent Review Committee (BIRC) Assessment
PFS was defined as time from the date of randomization to the date of first documented progression or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. Disease progression was assessed using the BIRC tumor assessment per RECIST 1.1. The distribution of PFS was estimated using the Kaplan-Meier method. Cox regression model stratified by randomization stratification factors was used to estimate the hazard ratio (HR) of PFS, along with 90% CI. As this was an estimation based approach, no p-value was provided.
Time frame: From randomization up to date of first documented progression or death, assessed up to approximately 1.8 years
Population: FAS including all subjects to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Exemestane | Progression-free Survival (PFS) Based on Blinded Independent Review Committee (BIRC) Assessment | 7.4 Months |
| Placebo + Exemestane | Progression-free Survival (PFS) Based on Blinded Independent Review Committee (BIRC) Assessment | 3.1 Months |
90% CI: [0.32, 0.67]
Secondary
Time to Definitive Deterioration of the Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score From Baseline
ECOG PS is a measure of functional status with scores ranging from 0 (fully active) to 5 (dead). Deterioration was considered definitive if no improvements in the ECOG PS status were observed after an instance of deterioration. Death was considered as worsening of the ECOG PS if it occurred close to the last assessment, where close is defined as twice the planned period between two assessments. Participants who died after more than twice the planned period between two assessments were censored at the date of their last assessment before the cut-off. Participants receiving any further anticancer therapy prior to definitive worsening were censored at their date of last assessment prior to start of therapy. Participants that had not worsened were censored at the date of last assessment prior to cut off. Time to definitive deterioration was estimated using the Kaplan-Meier method.
Time frame: From randomization up to definitive deterioration of the ECOG PS by one categotu of the score, assessed up to approximately 3.5 years
Population: FAS including all subjects to whom study treatment was assigned by randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Exemestane | Time to Definitive Deterioration of the Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score From Baseline | NA Months |
| Placebo + Exemestane | Time to Definitive Deterioration of the Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score From Baseline | NA Months |
Secondary
Time to Response (TTR) Based on BIRC Assessment
TTR was defined as the time between date of randomization until first documented response (CR or PR) according to RECIST 1.1 using BIRC assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 1.8 years
Population: Participants in the FAS with a confirmed CR or PR as per BIRC assessment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Exemestane | Time to Response (TTR) Based on BIRC Assessment | 57.0 Days |
| Placebo + Exemestane | Time to Response (TTR) Based on BIRC Assessment | 81.5 Days |
Secondary
Time to Response (TTR) Based on Local Radiology Review of Tumor Assessment
TTR was defined as the time between date of randomization until first documented response (CR or PR) according to RECIST 1.1 using local radiologist's/investigator's tumor assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 3.5 years
Population: Participants in the FAS with a confirmed CR or PR as per local radiologist's/investigator's tumor assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Exemestane | Time to Response (TTR) Based on Local Radiology Review of Tumor Assessment | 84.5 Days |
| Placebo + Exemestane | Time to Response (TTR) Based on Local Radiology Review of Tumor Assessment | 53.0 Days |
Post Hoc
All Collected Deaths
On-treatment deaths were collected from first dose of study medication to 30 days after the last dose of study medication for a maximum duration of approximately 3.5 years Post-treatment survival follow-up deaths were collected after 30 days post-treatment, for a maximum duration of approximately 3.8 years All deaths refer to the sum of on-treatment and post-treatment deaths
Time frame: On-treatment deaths: Up to 3.5 years. Post-treatment survival follow-up deaths: Up to 3.8 years
Population: Safety set including all subjects who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus + Exemestane | All Collected Deaths | On-treatment deaths | 3 Participants |
| Everolimus + Exemestane | All Collected Deaths | Post-treatment survival follow-up deaths | 41 Participants |
| Everolimus + Exemestane | All Collected Deaths | All deaths | 44 Participants |
| Placebo + Exemestane | All Collected Deaths | On-treatment deaths | 2 Participants |
| Placebo + Exemestane | All Collected Deaths | Post-treatment survival follow-up deaths | 43 Participants |
| Placebo + Exemestane | All Collected Deaths | All deaths | 45 Participants |