Breast Cancer
Conditions
Keywords
Breast Cancer, HER2+, mTOR, everolimus, RAD001, first line, metastatic, locally advanced, Trastuzumab, Paclitaxel, First Line Therapy, HER2 Positive, Metastatic Breast Cancer
Brief summary
The purpose of this Phase III study was to confirm the value of adding everolimus to weekly paclitaxel and trastuzumab as treatment of HER2-overexpressing metastatic breast cancer.
Interventions
DRUGEverolimus
Everolimus was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).
DRUGPlacebo
Everolimus placebo was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).
DRUGTrastuzumab
Trastuzumab, 2 mg/kg weekly was used intravenously.
DRUGPaclitaxel
Paclitaxel, 80 mg/m2 weekly was used intravenously.
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
* Adult Women (≥ 18 years old). * Histologically or cytologically confirmed invasive breast carcinoma with local recurrence or radiological evidence of metastatic disease. * Must have at least one lesion that can be accurately measured or bone lesions in the absence of measurable disease. * HER2+ patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive). * Prior trastuzumab and/or chemotherapy (taxanes included) as neo-adjuvant or adjuvant treatment is allowed but should be discontinued \> 12 months prior to randomization. * Prior treatment for breast cancer with endocrine therapy (adjuvant or metastatic settings) is allowed but should be discontinued at randomization. Patients treated with bisphosphonates at entry or who start bisphosphonates during study may continue this therapy during protocol treatment. * Documentation of negative pregnancy test. * Organ functions at time of inclusion.
Exclusion criteria
* Prior mTOR inhibitors for the treatment of cancer. * Other anticancer therapy for locally advanced or metastatic breast cancer except for prior hormonal therapy. * Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites, etc). * Radiotherapy to ≥ 25% of the bone marrow within 4 weeks prior to randomization * History of central nervous system metastasis. * Impairment of gastrointestinal (GI) function or GI disease or active ulceration of the upper gastrointestinal tract. * Serious peripheral neuropathy. * Cardiac disease or dysfunction. * Uncontrolled hypertension. * HIV. * Pregnant,
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - Full Population | date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to about 56 months | PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the full patient population. |
| Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - (Hormone Receptor (HR)-Negative Population | date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to about 56 months | PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the HR-negative patient population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) - Full Population | up to about 23 months | ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Overall Response Rate (ORR) - HR-negative Population | up to about 23 months | ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - Full Population | up to about 23 months | CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - HR-negative Population | up to about 23 months | CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Time to Overall Response Based on Investigator - Full Population | up to about 23 months | Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Time to Overall Response Based on Investigator - HR-negative Population | up to about 23 months | Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Overall Survival (OS) - Full Population | up to about 76 months | OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the full patient population. |
| Overall Response (OR) - HR-negative Population | up to about 23 months | OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. This was assessed in the HR-negative patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Everolimus Blood Level Concentrations at Steady States for Everolimus | predose, 2 hours post-dose at Cycle 2/Day 1, Cycle 2/Day 15, Cycle 2/ Day 22 | Blood levels at steady states for everolimus 10 mg/day and 5 mg/day. Only valid samples are included. Some patients had dose reduction to 5 mg daily dose therefore the everolimus blood concentration for them have been summarized separately. Cycle = 28 days |
| Paclitaxel Plasma Concentrations | Cycle 2/Day 15 (Pre-infusion and end of infusion) | Blood levels at steady states for everolimus/placebo |
| Trastuzumab Serum Concentrations | Cycle 4/Day 1 (Pre-infusion and end of infusion) | Blood levels at steady states for everolimus/placebo |
| Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - Full Population | up to about 56 months | Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed. |
| Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - HR-negative Population | up to about 56 months | Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed. |
| Overall Response (OR) - Full Population | up to about 23 months | OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Overall Survival (OS) - HR-negative Population | up to about 76 months | OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the HR-negative patient population. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, China, Colombia, Egypt, France, Germany, Greece, Hong Kong, Ireland, Italy, Japan, Lebanon, Mexico, Peru, Puerto Rico, Russia, South Africa, South Korea, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States, Venezuela
Participant flow
Recruitment details
717 patients were planned to be randomized. A total of 719 patients were randomized between 10-Sep-2009 and 16-Dec-2012. Not completed reasons = primary reasons for end of treatment
Participants by arm
| Arm | Count |
|---|---|
| Everolimus + Paclitaxel + Trastuzumab Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | 480 |
| Placebo + Paclitaxel + Trastuzumab Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | 239 |
| Total | 719 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal test procedure result(s) | 1 | 0 |
| Overall Study | Administrative problems | 39 | 23 |
| Overall Study | Adverse Event | 63 | 11 |
| Overall Study | Death | 12 | 0 |
| Overall Study | Disease progression | 259 | 162 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | New cancer therapy | 25 | 7 |
| Overall Study | Protocol Violation | 5 | 2 |
| Overall Study | Untreated | 8 | 1 |
| Overall Study | Withdrawal by Subject | 66 | 33 |
Baseline characteristics
| Characteristic | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab | Total |
|---|---|---|---|
| Age, Continuous | 53.4 Years STANDARD_DEVIATION 11.46 | 52.1 Years STANDARD_DEVIATION 11.63 | 53.0 Years STANDARD_DEVIATION 11.53 |
| Race/Ethnicity, Customized Asian | 198 Participants | 105 Participants | 303 Participants |
| Race/Ethnicity, Customized Black | 26 Participants | 12 Participants | 38 Participants |
| Race/Ethnicity, Customized Caucasian | 214 Participants | 97 Participants | 311 Participants |
| Race/Ethnicity, Customized Native American | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 39 Participants | 25 Participants | 64 Participants |
| Sex: Female, Male Female | 480 Participants | 239 Participants | 719 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 23 / 472 | 2 / 238 |
| other Total, other adverse events | 466 / 472 | 236 / 238 |
| serious Total, serious adverse events | 173 / 472 | 40 / 238 |
Outcome results
Primary
Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - Full Population
PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the full patient population.
Time frame: date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to about 56 months
Population: The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat principle patients will be analyzed according to the treatment and stratum they were assigned to at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - Full Population | 14.95 months |
| Placebo + Paclitaxel + Trastuzumab | Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - Full Population | 14.49 months |
p-value: 0.116695% CI: [0.73, 1.08]Log Rank
Primary
Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - (Hormone Receptor (HR)-Negative Population
PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the HR-negative patient population.
Time frame: date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to about 56 months
Population: HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - (Hormone Receptor (HR)-Negative Population | 20.27 Months |
| Placebo + Paclitaxel + Trastuzumab | Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - (Hormone Receptor (HR)-Negative Population | 13.08 Months |
p-value: 0.004995% CI: [0.48, 0.91]Log Rank
Secondary
Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - Full Population
CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
Time frame: up to about 23 months
Population: The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat principle patients will be analyzed according to the treatment and stratum they were assigned to at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - Full Population | 75.8 Percentage of participants |
| Placebo + Paclitaxel + Trastuzumab | Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - Full Population | 81.2 Percentage of participants |
p-value: 0.9573Exact Cochran-Mantel-Haenzel chi-square
Secondary
Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - HR-negative Population
CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
Time frame: up to about 23 months
Population: HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - HR-negative Population | 78.8 Percentage of participants |
| Placebo + Paclitaxel + Trastuzumab | Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - HR-negative Population | 79.6 Percentage of participants |
p-value: 0.6382Exact Cochran-Mantel-Haenzel chi-square
Secondary
Everolimus Blood Level Concentrations at Steady States for Everolimus
Blood levels at steady states for everolimus 10 mg/day and 5 mg/day. Only valid samples are included. Some patients had dose reduction to 5 mg daily dose therefore the everolimus blood concentration for them have been summarized separately. Cycle = 28 days
Time frame: predose, 2 hours post-dose at Cycle 2/Day 1, Cycle 2/Day 15, Cycle 2/ Day 22
Population: Safety Set: consists of all patients who received at least 1 dose of study treatment \& have at least 1 valid post-baseline safety assessment. Patients were analyzed according to the treatment actually received. If patient took at least 1 dose of treatment to which he/she was randomized then the treatment actually received was the rand. treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Everolimus Blood Level Concentrations at Steady States for Everolimus | Pre-dose (Cmin) @ C2D1 | 14.380 ng/mL | Standard Deviation 10.0169 |
| Everolimus + Paclitaxel + Trastuzumab | Everolimus Blood Level Concentrations at Steady States for Everolimus | 2 hrs post administration (C2h) @ C2D1 | 44.485 ng/mL | Standard Deviation 22.1986 |
| Everolimus + Paclitaxel + Trastuzumab | Everolimus Blood Level Concentrations at Steady States for Everolimus | Pre-dose (Cmin) @ C2D22 | 13.432 ng/mL | Standard Deviation 13.2782 |
| Everolimus + Paclitaxel + Trastuzumab | Everolimus Blood Level Concentrations at Steady States for Everolimus | Pre-dose (Cmin) @ C2D15 | 13.206 ng/mL | Standard Deviation 9.9821 |
| Everolimus + Paclitaxel + Trastuzumab | Everolimus Blood Level Concentrations at Steady States for Everolimus | 2 hrs post administration (C2h) @ C2D15 | 43.494 ng/mL | Standard Deviation 21.594 |
| Everolimus + Paclitaxel + Trastuzumab | Everolimus Blood Level Concentrations at Steady States for Everolimus | 2 hrs post administration (C2h) @ C2D22 | 43.947 ng/mL | Standard Deviation 28.0107 |
| Placebo + Paclitaxel + Trastuzumab | Everolimus Blood Level Concentrations at Steady States for Everolimus | Pre-dose (Cmin) @ C2D22 | 7.494 ng/mL | Standard Deviation 5.8503 |
| Placebo + Paclitaxel + Trastuzumab | Everolimus Blood Level Concentrations at Steady States for Everolimus | Pre-dose (Cmin) @ C2D1 | 7.959 ng/mL | Standard Deviation 8.1546 |
| Placebo + Paclitaxel + Trastuzumab | Everolimus Blood Level Concentrations at Steady States for Everolimus | Pre-dose (Cmin) @ C2D15 | 5.473 ng/mL | Standard Deviation 3.969 |
| Placebo + Paclitaxel + Trastuzumab | Everolimus Blood Level Concentrations at Steady States for Everolimus | 2 hrs post administration (C2h) @ C2D1 | 23.449 ng/mL | Standard Deviation 10.4112 |
| Placebo + Paclitaxel + Trastuzumab | Everolimus Blood Level Concentrations at Steady States for Everolimus | 2 hrs post administration (C2h) @ C2D15 | 20.329 ng/mL | Standard Deviation 7.9518 |
| Placebo + Paclitaxel + Trastuzumab | Everolimus Blood Level Concentrations at Steady States for Everolimus | 2 hrs post administration (C2h) @ C2D22 | 22.192 ng/mL | Standard Deviation 10.9277 |
Secondary
Overall Response (OR) - Full Population
OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
Time frame: up to about 23 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Overall Response (OR) - Full Population | Complete Response (CR) | 5.6 Percentage of participants |
| Everolimus + Paclitaxel + Trastuzumab | Overall Response (OR) - Full Population | Partial Response (PR) | 61.5 Percentage of participants |
| Placebo + Paclitaxel + Trastuzumab | Overall Response (OR) - Full Population | Complete Response (CR) | 5.9 Percentage of participants |
| Placebo + Paclitaxel + Trastuzumab | Overall Response (OR) - Full Population | Partial Response (PR) | 63.2 Percentage of participants |
Secondary
Overall Response (OR) - HR-negative Population
OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. This was assessed in the HR-negative patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
Time frame: up to about 23 months
Population: HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Overall Response (OR) - HR-negative Population | Complete Response (CR) | 7.7 Percentage of participants |
| Everolimus + Paclitaxel + Trastuzumab | Overall Response (OR) - HR-negative Population | Partial Response (PR) | 65.4 Percentage of participants |
| Placebo + Paclitaxel + Trastuzumab | Overall Response (OR) - HR-negative Population | Complete Response (CR) | 2.9 Percentage of participants |
| Placebo + Paclitaxel + Trastuzumab | Overall Response (OR) - HR-negative Population | Partial Response (PR) | 68.0 Percentage of participants |
Secondary
Overall Response Rate (ORR) - Full Population
ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
Time frame: up to about 23 months
Population: The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat principle patients will be analyzed according to the treatment and stratum they were assigned to at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Overall Response Rate (ORR) - Full Population | 67.1 Percentage of participants |
| Placebo + Paclitaxel + Trastuzumab | Overall Response Rate (ORR) - Full Population | 69.0 Percentage of participants |
p-value: 0.7276Exact Cochran-Mantel-Haenzel chi-square
Secondary
Overall Response Rate (ORR) - HR-negative Population
ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
Time frame: up to about 23 months
Population: HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Overall Response Rate (ORR) - HR-negative Population | 73.1 Percentage of participants |
| Placebo + Paclitaxel + Trastuzumab | Overall Response Rate (ORR) - HR-negative Population | 70.9 Percentage of participants |
p-value: 0.4085Exact Cochran-Mantel-Haenzel chi-square
Secondary
Overall Survival (OS) - Full Population
OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the full patient population.
Time frame: up to about 76 months
Population: The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat principle patients will be analyzed according to the treatment and stratum they were assigned to at randomization. Due to the exploratory nature of the OS analysis, OS was not statistically tested
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Overall Survival (OS) - Full Population | 48.56 Months |
| Placebo + Paclitaxel + Trastuzumab | Overall Survival (OS) - Full Population | 49.97 Months |
Secondary
Overall Survival (OS) - HR-negative Population
OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the HR-negative patient population.
Time frame: up to about 76 months
Population: HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline. Due to the exploratory nature of the OS analysis, OS was not statistically tested.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Overall Survival (OS) - HR-negative Population | 56.97 Months |
| Placebo + Paclitaxel + Trastuzumab | Overall Survival (OS) - HR-negative Population | 41.63 Months |
Secondary
Paclitaxel Plasma Concentrations
Blood levels at steady states for everolimus/placebo
Time frame: Cycle 2/Day 15 (Pre-infusion and end of infusion)
Population: Safety Set: consists of all patients who received at least 1 dose of study treatment \& have at least 1 valid post-baseline safety assessment. Patients were analyzed according to the treatment actually received. If patient took at least 1 dose of treatment to which he/she was randomized then the treatment actually received was the rand. treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Paclitaxel Plasma Concentrations | Pre-infusion (Cmin) @ C2D15 | 1.424 ng/mL | Standard Deviation 5.8645 |
| Everolimus + Paclitaxel + Trastuzumab | Paclitaxel Plasma Concentrations | End of infusion (Cmax) @ C2D15 | 5159.338 ng/mL | Standard Deviation 15473.636 |
| Placebo + Paclitaxel + Trastuzumab | Paclitaxel Plasma Concentrations | End of infusion (Cmax) @ C2D15 | 4296.697 ng/mL | Standard Deviation 7431.0799 |
| Placebo + Paclitaxel + Trastuzumab | Paclitaxel Plasma Concentrations | Pre-infusion (Cmin) @ C2D15 | 0 ng/mL | Standard Deviation 0 |
Secondary
Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - Full Population
Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed.
Time frame: up to about 56 months
Population: The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat principle patients will be analyzed according to the treatment and stratum they were assigned to at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - Full Population | 39.20 months |
| Placebo + Paclitaxel + Trastuzumab | Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - Full Population | NA months |
Secondary
Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - HR-negative Population
Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed.
Time frame: up to about 56 months
Population: HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - HR-negative Population | NA months |
| Placebo + Paclitaxel + Trastuzumab | Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - HR-negative Population | NA months |
Secondary
Time to Overall Response Based on Investigator - Full Population
Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
Time frame: up to about 23 months
Population: The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat principle patients will be analyzed according to the treatment and stratum they were assigned to at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Time to Overall Response Based on Investigator - Full Population | 2.10 months |
| Placebo + Paclitaxel + Trastuzumab | Time to Overall Response Based on Investigator - Full Population | 2.00 months |
Secondary
Time to Overall Response Based on Investigator - HR-negative Population
Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
Time frame: up to about 23 months
Population: HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Time to Overall Response Based on Investigator - HR-negative Population | 1.94 months |
| Placebo + Paclitaxel + Trastuzumab | Time to Overall Response Based on Investigator - HR-negative Population | 1.97 months |
Secondary
Trastuzumab Serum Concentrations
Blood levels at steady states for everolimus/placebo
Time frame: Cycle 4/Day 1 (Pre-infusion and end of infusion)
Population: Safety Set: consists of all patients who received at least 1 dose of study treatment \& have at least 1 valid post-baseline safety assessment. Patients were analyzed according to the treatment actually received. If patient took at least 1 dose of treatment to which he/she was randomized then the treatment actually received was the rand. treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus + Paclitaxel + Trastuzumab | Trastuzumab Serum Concentrations | End of infusion (Cmax) @ C4D1 | 64.296 microgram/ml | Standard Deviation 23.4635 |
| Everolimus + Paclitaxel + Trastuzumab | Trastuzumab Serum Concentrations | Pre-infusion (Cmin) @ C4D1 | 26.606 microgram/ml | Standard Deviation 9.6548 |
| Placebo + Paclitaxel + Trastuzumab | Trastuzumab Serum Concentrations | Pre-infusion (Cmin) @ C4D1 | 29.180 microgram/ml | Standard Deviation 12.1252 |
| Placebo + Paclitaxel + Trastuzumab | Trastuzumab Serum Concentrations | End of infusion (Cmax) @ C4D1 | 67.643 microgram/ml | Standard Deviation 20.8852 |