Post Menopausal Breast Cancer
Conditions
Keywords
post menopausal, advanced breast cancer, metastatic breast cancer, everolimus, exemestane, mTor inhibitor, endocrine therapy, human epidermal growth factor, estrogen receptor positive, adult, CRAD001
Brief summary
This international, multi-center, open-label, single-arm study evaluated the safety and tolerability profile of everolimus in post-menopausal women with HR positive, HER2 negative locally advanced or metastatic breast cancer after documented recurrence or progression following a non-steroidal aromatase inhibitors (NSAI) therapy in Novartis Oncology emergent growth market (EGM) countries.Data was presented by Asian countries vs Non-Asian countries to confirm no difference in safety and efficacy. Summary statistics were presented.
Interventions
DRUGeverolimus
one 10 mg tablet or two 5 mg tablets of everolimus were administered orally once daily on a continuous dosing schedule starting on Day 1
DRUGexemestane
25 mg tablet was administered orally once daily on a continuous dosing schedule starting on Day 1
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Postmenopausal women with metastatic, recurrent or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy. * Histological or cytological confirmation of hormone-receptor positive (HR+) breast cancer. * Disease refractory to non-steroidal aromatase inhibitors, defined as: * Recurrence while on, or within 12 months (365 days) of completion of adjuvant therapy with letrozole or anastrozole, or * Progression while on, or within one month (30 days) of completion of letrozole or anastrozole treatment for locally advanced or metastatic breast cancer (ABC). * Radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to enrolment. * Patients must have had: * At least one lesion that could have been accurately measured in at least one dimension * 20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT or MRI, or * Bone lesions: lytic or mixed (lytic + blastic) in the absence of measurable disease as defined above. * Adequate bone marrow, coagulation, liver and renal function. * ECOG performance status ≤ 2.
Exclusion criteria
* Patients overexpressing HER2 by local laboratory testing (IHC 3+ staining or in situ hybridization positive). Patients with IHC 2+ must have a negative in situ hybridization test. * Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites). * Patients with more than one prior chemotherapy line for ABC. A chemotherapy line is an anticancer regimen(s) that contained at least 1 cytotoxic chemotherapy agent, given for a minimum of 21 days. * Previous treatment with mTOR inhibitors. * Known hypersensitivity to mTOR inhibitors, e.g. Sirolimus (rapamycin). * Patients with a known history of HIV seropositivity. Screening for HIV infection at baseline was not required. * Patient who were being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A * History of brain or other CNS metastases, including leptomeningeal metastasis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | Baseline up to approximately 43 weeks for Asian countires and 32 weeks for Non-Asian countries including a 30 day post treatment follow up period | Adverse events (AEs), serious adverse events (SAEs), changes from baseline in vital signs and laboratory results (hematology, blood chemistry, lipid profile) qualifying and reported as AEs. Although a patient might had two or more adverse events the patient is only counted once in a category. The same patient might appear in different categories. AESI: Adverse events of special interest. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Response Rates (Best Overall and Overall) | Baseline up to approximately 43 weeks for Asian countires and 32 weeks for Non-Asian countries | The best overall response for each patient is determined from the sequence of investigator overall lesion responses according to RECIST 1.1: Complete Response (CR)=disappearance of target lesions, Partial Response (PR) was \>=30% decrease in sum of diameter of lesions, Progressive Disease (PD) was \>=20% decrease in sum of diameter of lesions, Stable Disease (SD) does not qualify for PR, CR or PD, Unknown=not documented or assessed. To be assigned a best overall response of CR at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best overall response of PR at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required. The Overall response rate (ORR) is the percentage of patients with a best overall response of confirmed complete (CR) or partial (PR) response. The 95% confidence intervals (CI) were computed using the Clopper-Pearson method |
| Percentage of Participants Clinical Benefit Rate | Baseline up to approximately 43 weeks for Asian countires and 32 weeks for Non-Asian countries | Clinical benefit rate: Patients with best overall response rate of CR (any duration), PR (any duration) and SD with duration of 24 weeks or longer according to RECIST 1.1 criteria: Complete Response (CR)=disappearance of target lesions, Partial Response (PR) was \>=30% decrease in sum of diameter of lesions, Progressive Disease (PD) was \>=20% decrease in sum of diameter of lesions, Stable Disease (SD) does not qualify for PR, CR or PD, Unknown=not documented or assessed. Best overall response of CR = at least two determinations of CR at least 4 weeks apart before progression are required. Best overall response of PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required. The Overall response rate (ORR) is the percentage of patients with a best overall response of confirmed complete (CR) or partial (PR) response. The 95% confidence intervals (CI) were computed using the Clopper-Pearson method. |
| Progression Free Survival (PFS) | Baseline up to approximately 43 weeks for Asian countires and 40 weeks for Non-Asian countries | PFS is time from date of start of treatment to date of disease progression or death due to any cause, whichever occurs first. b Percentiles with 95% CIs are calculated from PROC LIFETEST output using method of Brookmeyer and Crowley (1982) |
| Percent of Participants Event-free Probability Estimates of Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status | Baseline up to approximately 50 weeks | Time to deterioration of ECOG performance status, from baseline will be assessed using the ECOG Performance Status Scale (Oken, 1982). Time to deterioration is the time from date of start of treatment to the date of the event defined as deterioration. Deterioration is defined as an increase in performance status from 0 to 2 or greater, an increase in performance status from 1-2 to 3 or greater, or death due to any cause. Event-free probability estimate is the estimated probability that a patient will remain event-free up to the specified time point. Event-free probability estimates were are obtained from the Kaplan-Meier survival estimates. |
Countries
Australia, India, Indonesia, Jordan, Malaysia, Morocco, South Africa, South Korea, Taiwan, Thailand, Tunisia, Turkey (Türkiye), Vietnam
Participant flow
Pre-assignment details
Three hundred eleven participants were screened and 235 enrolled in Asian and non-Asian countries. Primary reason for discontinuation was presented.
Participants by arm
| Arm | Count |
|---|---|
| Asian Everolimus + Exemestane Everolimus (10 Mg) and exemestane (25 mg) tablets taken orally in combination once daily. Participants in Asian countries: Indonesia, India, Vietnam, Turkey, South Korea, Thailand, Malaysia, Taiwan or Jordan. | 199 |
| Non-Asian Everolimus + Exemestane Everolimus (10 mg) and exemestane (25 mg) tablets taken orally in combination once daily. Participants in Non-Asian countries: Australia, Morocco, South Africa or Tunisia. | 36 |
| Total | 235 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal lab value(s) | 2 | 0 |
| Overall Study | Administrative problems | 1 | 0 |
| Overall Study | Changes in the patient's condition | 2 | 1 |
| Overall Study | Consent withdrawal | 14 | 2 |
| Overall Study | Death | 3 | 0 |
| Overall Study | Disease Progression | 133 | 22 |
| Overall Study | Everolimus dose interrupt > 4 wks | 9 | 0 |
| Overall Study | Inter-current illness | 0 | 1 |
| Overall Study | Lost to Follow-up | 3 | 0 |
| Overall Study | Patient is switched to commercial drug | 16 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Tx duration completed per EAP | 0 | 1 |
| Overall Study | Unacceptable AEs | 15 | 8 |
Baseline characteristics
| Characteristic | Non-Asian Everolimus + Exemestane | Asian Everolimus + Exemestane | Total |
|---|---|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 10.26 | 58.4 years STANDARD_DEVIATION 10 | 58.8 years STANDARD_DEVIATION 10.05 |
| Race/Ethnicity, Customized Asian | 3 participants | 156 participants | 159 participants |
| Race/Ethnicity, Customized Caucasian | 27 participants | 7 participants | 34 participants |
| Race/Ethnicity, Customized Other | 6 participants | 36 participants | 42 participants |
| Sex/Gender, Customized Females | 36 Participants | 199 Participants | 235 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 199 | 4 / 36 |
| other Total, other adverse events | 192 / 199 | 36 / 36 |
| serious Total, serious adverse events | 59 / 199 | 16 / 36 |
Outcome results
Primary
Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades
Adverse events (AEs), serious adverse events (SAEs), changes from baseline in vital signs and laboratory results (hematology, blood chemistry, lipid profile) qualifying and reported as AEs. Although a patient might had two or more adverse events the patient is only counted once in a category. The same patient might appear in different categories. AESI: Adverse events of special interest.
Time frame: Baseline up to approximately 43 weeks for Asian countires and 32 weeks for Non-Asian countries including a 30 day post treatment follow up period
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 serious TEAE (STEAE) | 59 Participants |
| Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | 1 TE AESI | 172 Participants |
| Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | no TEAE | 4 Participants |
| Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 TEAE | 195 Participants |
| Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 drug-related TEAE | 185 Participants |
| Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | STEAE leading to death | 6 Participants |
| Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | Non-fatal STEAE | 53 Participants |
| Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 drug-related STEAE | 28 Participants |
| Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 drug-related STEAE - death | 2 Participants |
| Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 drug-related non-fatal STEAE | 26 Participants |
| Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | TEAE leading to permanent tx discontinuation | 25 Participants |
| Non-Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | STEAE leading to death | 4 Participants |
| Non-Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 drug-related STEAE | 8 Participants |
| Non-Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 serious TEAE (STEAE) | 16 Participants |
| Non-Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | TEAE leading to permanent tx discontinuation | 11 Participants |
| Non-Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | 1 TE AESI | 34 Participants |
| Non-Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 drug-related STEAE - death | 1 Participants |
| Non-Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | no TEAE | 0 Participants |
| Non-Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 drug-related TEAE | 33 Participants |
| Non-Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | Non-fatal STEAE | 12 Participants |
| Non-Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 TEAE | 36 Participants |
| Non-Asian Everolimus + Exemestane | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 drug-related non-fatal STEAE | 7 Participants |
| Total | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 TEAE | 231 Participants |
| Total | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 drug-related TEAE | 218 Participants |
| Total | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 serious TEAE (STEAE) | 75 Participants |
| Total | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | STEAE leading to death | 10 Participants |
| Total | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 drug-related non-fatal STEAE | 33 Participants |
| Total | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | Non-fatal STEAE | 65 Participants |
| Total | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | 1 TE AESI | 206 Participants |
| Total | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 drug-related STEAE | 36 Participants |
| Total | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | no TEAE | 4 Participants |
| Total | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | at least 1 drug-related STEAE - death | 3 Participants |
| Total | Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | TEAE leading to permanent tx discontinuation | 36 Participants |
Secondary
Percentage of Participants Clinical Benefit Rate
Clinical benefit rate: Patients with best overall response rate of CR (any duration), PR (any duration) and SD with duration of 24 weeks or longer according to RECIST 1.1 criteria: Complete Response (CR)=disappearance of target lesions, Partial Response (PR) was \>=30% decrease in sum of diameter of lesions, Progressive Disease (PD) was \>=20% decrease in sum of diameter of lesions, Stable Disease (SD) does not qualify for PR, CR or PD, Unknown=not documented or assessed. Best overall response of CR = at least two determinations of CR at least 4 weeks apart before progression are required. Best overall response of PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required. The Overall response rate (ORR) is the percentage of patients with a best overall response of confirmed complete (CR) or partial (PR) response. The 95% confidence intervals (CI) were computed using the Clopper-Pearson method.
Time frame: Baseline up to approximately 43 weeks for Asian countires and 32 weeks for Non-Asian countries
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Asian Everolimus + Exemestane | Percentage of Participants Clinical Benefit Rate | 48.2 Percentage of participants |
| Non-Asian Everolimus + Exemestane | Percentage of Participants Clinical Benefit Rate | 30.6 Percentage of participants |
| Total | Percentage of Participants Clinical Benefit Rate | 45.5 Percentage of participants |
Secondary
Percentage of Participants Response Rates (Best Overall and Overall)
The best overall response for each patient is determined from the sequence of investigator overall lesion responses according to RECIST 1.1: Complete Response (CR)=disappearance of target lesions, Partial Response (PR) was \>=30% decrease in sum of diameter of lesions, Progressive Disease (PD) was \>=20% decrease in sum of diameter of lesions, Stable Disease (SD) does not qualify for PR, CR or PD, Unknown=not documented or assessed. To be assigned a best overall response of CR at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best overall response of PR at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required. The Overall response rate (ORR) is the percentage of patients with a best overall response of confirmed complete (CR) or partial (PR) response. The 95% confidence intervals (CI) were computed using the Clopper-Pearson method
Time frame: Baseline up to approximately 43 weeks for Asian countires and 32 weeks for Non-Asian countries
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Asian Everolimus + Exemestane | Percentage of Participants Response Rates (Best Overall and Overall) | Complete response (CR) | 1.5 Percentage of participants |
| Asian Everolimus + Exemestane | Percentage of Participants Response Rates (Best Overall and Overall) | Unknown (UNK) | 9.0 Percentage of participants |
| Asian Everolimus + Exemestane | Percentage of Participants Response Rates (Best Overall and Overall) | Stable disease (SD) | 51.3 Percentage of participants |
| Asian Everolimus + Exemestane | Percentage of Participants Response Rates (Best Overall and Overall) | Overall response rate (ORR: CR+PR) | 21.6 Percentage of participants |
| Asian Everolimus + Exemestane | Percentage of Participants Response Rates (Best Overall and Overall) | Progressive disease (PD) | 18.1 Percentage of participants |
| Asian Everolimus + Exemestane | Percentage of Participants Response Rates (Best Overall and Overall) | Partial response (PR) | 20.1 Percentage of participants |
| Non-Asian Everolimus + Exemestane | Percentage of Participants Response Rates (Best Overall and Overall) | Stable disease (SD) | 63.9 Percentage of participants |
| Non-Asian Everolimus + Exemestane | Percentage of Participants Response Rates (Best Overall and Overall) | Complete response (CR) | 0.00 Percentage of participants |
| Non-Asian Everolimus + Exemestane | Percentage of Participants Response Rates (Best Overall and Overall) | Partial response (PR) | 8.3 Percentage of participants |
| Non-Asian Everolimus + Exemestane | Percentage of Participants Response Rates (Best Overall and Overall) | Progressive disease (PD) | 19.4 Percentage of participants |
| Non-Asian Everolimus + Exemestane | Percentage of Participants Response Rates (Best Overall and Overall) | Unknown (UNK) | 8.3 Percentage of participants |
| Non-Asian Everolimus + Exemestane | Percentage of Participants Response Rates (Best Overall and Overall) | Overall response rate (ORR: CR+PR) | 8.3 Percentage of participants |
| Total | Percentage of Participants Response Rates (Best Overall and Overall) | Unknown (UNK) | 8.9 Percentage of participants |
| Total | Percentage of Participants Response Rates (Best Overall and Overall) | Progressive disease (PD) | 18.3 Percentage of participants |
| Total | Percentage of Participants Response Rates (Best Overall and Overall) | Overall response rate (ORR: CR+PR) | 19.6 Percentage of participants |
| Total | Percentage of Participants Response Rates (Best Overall and Overall) | Partial response (PR) | 18.3 Percentage of participants |
| Total | Percentage of Participants Response Rates (Best Overall and Overall) | Stable disease (SD) | 53.2 Percentage of participants |
| Total | Percentage of Participants Response Rates (Best Overall and Overall) | Complete response (CR) | 1.3 Percentage of participants |
Secondary
Percent of Participants Event-free Probability Estimates of Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status
Time to deterioration of ECOG performance status, from baseline will be assessed using the ECOG Performance Status Scale (Oken, 1982). Time to deterioration is the time from date of start of treatment to the date of the event defined as deterioration. Deterioration is defined as an increase in performance status from 0 to 2 or greater, an increase in performance status from 1-2 to 3 or greater, or death due to any cause. Event-free probability estimate is the estimated probability that a patient will remain event-free up to the specified time point. Event-free probability estimates were are obtained from the Kaplan-Meier survival estimates.
Time frame: Baseline up to approximately 50 weeks
Population: Number of participants meeting criteria differed at visits
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Asian Everolimus + Exemestane | Percent of Participants Event-free Probability Estimates of Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status | Week 50 n=58,7,65 | 90.6 percent of participants |
| Asian Everolimus + Exemestane | Percent of Participants Event-free Probability Estimates of Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status | Week 20 n=134,18,152 | 95.0 percent of participants |
| Asian Everolimus + Exemestane | Percent of Participants Event-free Probability Estimates of Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status | Week 0 n=199,36,235 | 100.0 percent of participants |
| Non-Asian Everolimus + Exemestane | Percent of Participants Event-free Probability Estimates of Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status | Week 50 n=58,7,65 | 70.4 percent of participants |
| Non-Asian Everolimus + Exemestane | Percent of Participants Event-free Probability Estimates of Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status | Week 0 n=199,36,235 | 100.0 percent of participants |
| Non-Asian Everolimus + Exemestane | Percent of Participants Event-free Probability Estimates of Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status | Week 20 n=134,18,152 | 79.8 percent of participants |
| Total | Percent of Participants Event-free Probability Estimates of Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status | Week 50 n=58,7,65 | 87.6 percent of participants |
| Total | Percent of Participants Event-free Probability Estimates of Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status | Week 20 n=134,18,152 | 92.7 percent of participants |
| Total | Percent of Participants Event-free Probability Estimates of Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status | Week 0 n=199,36,235 | 100.00 percent of participants |
Secondary
Progression Free Survival (PFS)
PFS is time from date of start of treatment to date of disease progression or death due to any cause, whichever occurs first. b Percentiles with 95% CIs are calculated from PROC LIFETEST output using method of Brookmeyer and Crowley (1982)
Time frame: Baseline up to approximately 43 weeks for Asian countires and 40 weeks for Non-Asian countries
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Asian Everolimus + Exemestane | Progression Free Survival (PFS) | 40.6 weeks |
| Non-Asian Everolimus + Exemestane | Progression Free Survival (PFS) | 37.0 weeks |
| Total | Progression Free Survival (PFS) | 40.6 weeks |