Breast Cancer
Conditions
Brief summary
This 2 arm study assessed the safety and efficacy of adding intravenous trastuzumab (Herceptin®) to daily oral anastrozole (Arimidex®) tablets as first- and second-line treatment in postmenopausal patients with human epidermal growth factor receptor-2 (HER2) overexpressing metastatic breast cancer (ER+ve and/or PR+ve). Patients were randomized to receive either anastrazole 1 mg per os (po) daily, or anastrazole 1 mg po daily + a loading dose of Herceptin® 4 mg/kg intravenous (iv) followed by weekly doses of Herceptin® 2 mg/kg iv. The anticipated time on study treatment was until disease progression, and the target sample size was 100-500 individuals.
Interventions
4mg/kg iv loading dose, followed by 2mg/kg iv weekly
DRUGanastrazole (Arimidex®)
1 mg tablet taken orally daily
Sponsors
Genentech, Inc.
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* postmenopausal women; * metastatic breast cancer suitable for endocrine therapy; * positive hormone receptor status; * Human epidermal growth factor receptor 2 (HER2) overexpression.
Exclusion criteria
* patients on hormone replacement therapy; * previous chemotherapy for metastatic disease; * uncontrolled cardiac disease and history of cardiac failure.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 24 Months, End of Study (Up to 5 years) | PFS was assessed by the investigator based on World Health Organization (WHO) criteria using radiographic tumor evaluations. Disease progression was defined as the appearance of any new lesion not previously identified or an estimated increase of 25% or more in existent bidimensionally or unidimensionally measurable lesions or progression of an existing non-measurable lesion. For bidimensionally measurable malignant lesions with an area of at least 2.0 centimeters squared (cm\^2) an increase of 1.0 cm\^2 was required and for unidimensionally measurable lesions of 1.0 cm or less an increase of 0.5 cm was required. PFS was defined as the number of days between date of randomization and date of documented disease progression or date of death. Kaplan Meier estimates of PFS are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response at 24 Months | 24 Months | Duration of response was defined as the number of days from the day complete response or partial response was first noted to the day of progression of disease, death or last follow-up. |
| Time to Response at 24 Months | 24 Months | Time to response was defined as the number of days from the day of randomization to the day complete response or partial response was first noted. |
| Overall Survival at 24 Months | 24 Months | Overall Survival is defined as the number of days from randomization to death. |
| Percentage of Participants With Two-Year Survival | 24 Months | — |
| Percentage of Participants With Overall Tumor Response at 24 Months | 24 Months | Tumor Response levels were determined by the investigator and an Independent Response Evaluation Committee and Reconciled. Overall Response was defined as either complete response or partial response. |
| Percentage of Participants With Best Tumor Response at 24 Months | 24 Months | Tumor Response levels were determined by the investigator and an Independent Response Evaluation Committee and Reconciled. Best Response was defined as the best response a patient achieves in the study. |
| Percentage of Participants With Clinical Benefit | 24 Months, End of Study (Up to 5 years) | Clinical Benefit was defined as stable disease for ≥ six months or complete response or partial response. |
| Duration of Response at End of Study | End of Study (Up to 5 years) | Duration of response was defined as the number of days from the day complete response or partial response was first noted to the day of progression of disease, death or last follow-up. |
| Time to Response at End of Study | End of Study (Up to 5 years) | Time to response was defined as the number of days from the day of randomization to the day complete response or partial response was first noted. |
| Percentage of Participants With Overall Tumor Response at End of Study | End of Study (Up to 5 years) | Tumor Response levels were determined by the investigator and an Independent Response Evaluation Committee and Reconciled. Overall Response was defined as either complete response or partial response. |
| Percentage of Participants With Best Tumor Response at End of Study | End of Study (Up to 5 years) | Tumor Response levels were determined by the investigator and an Independent Response Evaluation Committee and Reconciled. Best Response was defined as the best response a patient achieves in the study. |
| Number of Participants With Adverse Events | Throughout the Study (Up to 5 years) | Number of participants with adverse events as a measure for safety as assessed by the collection of adverse events, laboratory tests for Hematology and Serum Chemistry, clinical assessments and cardiac monitoring. |
| Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Final Visit Compared to Baseline | Baseline, Final Visit (Up to 24 Months) | Participants rated their performance status using the ECOG Questionnaire on the following scale: 0=Fully active, perform all pre-disease activities without restriction; 1=Restricted in physically strenuous activity but ambulatory, carry out work of a light or sedentary nature; 2=Ambulatory, capable of self-care, unable to carry out any work activities, up and about more than \>50% of waking hours; 3=Capable of limited self-care, confined to bed or chair \>50% of waking hours; 4=Completely disabled, not capable of any self-care, totally confined to bed or chair; 5=Dead. The percentage of participants in the following categories: Improved: Score decrease from baseline. Unchanged: Score the same as baseline. Worse: Score increase from baseline. |
Countries
Australia, Brazil, Bulgaria, Canada, China, France, Germany, Hong Kong, Hungary, India, Israel, Italy, Lithuania, Mexico, Netherlands, Norway, Poland, Russia, South Africa, Spain, Sweden, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
208 participants were randomized. 1 participant did not receive study drug. After the completion of the 24 month Main Phase or disease progression, participants in the anastrozole-alone treatment arm entered the Extension Phase where they received trastuzumab + anastrozole.
Participants by arm
| Arm | Count |
|---|---|
| Trastuzumab + Anastrozole Trastuzumab 4 mg/kg loading dose intravenous (iv) over 90 minutes, followed by weekly doses of 2 mg/kg iv over 30 minutes plus 1 mg oral dose of anastrozole every day for 24 Months in the Main phase and in the Extension Phase. | 103 |
| Anastrozole 1 mg oral dose of anastrozole every day for 24 Months in the Main phase. In the Extension Phase participants could cross-over to also receive trastuzumab 4 mg/kg initial loading dose intravenous (iv) over 90 minutes, followed by weekly doses of 2 mg/kg iv over 30 minutes. | 104 |
| Total | 207 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension Phase | Adverse Event | 1 | 3 |
| Extension Phase | Death | 0 | 1 |
| Extension Phase | Insufficient Therapeutic Response | 1 | 44 |
| Extension Phase | Other | 1 | 1 |
| Extension Phase | Refused Treatment | 0 | 2 |
| Main Phase: 24 Months | Adverse Event | 6 | 0 |
| Main Phase: 24 Months | Death | 0 | 3 |
| Main Phase: 24 Months | Failure to Return | 1 | 1 |
| Main Phase: 24 Months | Insufficient Therapeutic Response | 75 | 91 |
| Main Phase: 24 Months | Other | 1 | 0 |
| Main Phase: 24 Months | Other Protocol Violation | 1 | 0 |
| Main Phase: 24 Months | Refused Treatment | 3 | 4 |
| Main Phase: 24 Months | Violation of Selection Criteria at Entry | 0 | 1 |
Baseline characteristics
| Characteristic | Trastuzumab + Anastrozole | Anastrozole | Total |
|---|---|---|---|
| Age Continuous | 57.4 years STANDARD_DEVIATION 10.6 | 55.5 years STANDARD_DEVIATION 10.7 | 56.5 years STANDARD_DEVIATION 10.7 |
| Sex: Female, Male Female | 103 Participants | 104 Participants | 207 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 |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 89 / 103 | 68 / 104 | 40 / 58 |
| serious Total, serious adverse events | 25 / 103 | 6 / 104 | 8 / 58 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS was assessed by the investigator based on World Health Organization (WHO) criteria using radiographic tumor evaluations. Disease progression was defined as the appearance of any new lesion not previously identified or an estimated increase of 25% or more in existent bidimensionally or unidimensionally measurable lesions or progression of an existing non-measurable lesion. For bidimensionally measurable malignant lesions with an area of at least 2.0 centimeters squared (cm\^2) an increase of 1.0 cm\^2 was required and for unidimensionally measurable lesions of 1.0 cm or less an increase of 0.5 cm was required. PFS was defined as the number of days between date of randomization and date of documented disease progression or date of death. Kaplan Meier estimates of PFS are presented.
Time frame: 24 Months, End of Study (Up to 5 years)
Population: Full analysis population included all randomized participants who received study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Trastuzumab + Anastrozole | Progression Free Survival (PFS) | 24 Months | 4.8 Months |
| Trastuzumab + Anastrozole | Progression Free Survival (PFS) | End of Study | 5.8 Months |
| Anastrozole | Progression Free Survival (PFS) | 24 Months | 2.4 Months |
| Anastrozole | Progression Free Survival (PFS) | End of Study | 2.9 Months |
Secondary
Duration of Response at 24 Months
Duration of response was defined as the number of days from the day complete response or partial response was first noted to the day of progression of disease, death or last follow-up.
Time frame: 24 Months
Population: Participants from the Full Analysis population (all randomized participants who received study drug) evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab + Anastrozole | Duration of Response at 24 Months | 9.5 Months |
| Anastrozole | Duration of Response at 24 Months | 10.0 Months |
Secondary
Duration of Response at End of Study
Duration of response was defined as the number of days from the day complete response or partial response was first noted to the day of progression of disease, death or last follow-up.
Time frame: End of Study (Up to 5 years)
Population: Participants from the Full Analysis population (all randomized participants who received study drug) evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab + Anastrozole | Duration of Response at End of Study | 12.3 Months |
| Anastrozole | Duration of Response at End of Study | 8.2 Months |
Secondary
Number of Participants With Adverse Events
Number of participants with adverse events as a measure for safety as assessed by the collection of adverse events, laboratory tests for Hematology and Serum Chemistry, clinical assessments and cardiac monitoring.
Time frame: Throughout the Study (Up to 5 years)
Population: Safety population included all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab + Anastrozole | Number of Participants With Adverse Events | 90 Participants |
| Anastrozole | Number of Participants With Adverse Events | 68 Participants |
Secondary
Overall Survival at 24 Months
Overall Survival is defined as the number of days from randomization to death.
Time frame: 24 Months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab + Anastrozole | Overall Survival at 24 Months | 28.5 Months |
| Anastrozole | Overall Survival at 24 Months | 23.9 Months |
Secondary
Percentage of Participants With Best Tumor Response at 24 Months
Tumor Response levels were determined by the investigator and an Independent Response Evaluation Committee and Reconciled. Best Response was defined as the best response a patient achieves in the study.
Time frame: 24 Months
Population: Participants from the Full Analysis Population (all randomized participants who received study drug) evaluable for response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab + Anastrozole | Percentage of Participants With Best Tumor Response at 24 Months | Partial Response | 20.3 Percentage of participants |
| Trastuzumab + Anastrozole | Percentage of Participants With Best Tumor Response at 24 Months | Progressive Disease | 40.5 Percentage of participants |
| Trastuzumab + Anastrozole | Percentage of Participants With Best Tumor Response at 24 Months | Stable Disease | 37.8 Percentage of participants |
| Trastuzumab + Anastrozole | Percentage of Participants With Best Tumor Response at 24 Months | Response not assessed | 1.4 Percentage of participants |
| Trastuzumab + Anastrozole | Percentage of Participants With Best Tumor Response at 24 Months | Complete Response | 0.0 Percentage of participants |
| Anastrozole | Percentage of Participants With Best Tumor Response at 24 Months | Response not assessed | 5.5 Percentage of participants |
| Anastrozole | Percentage of Participants With Best Tumor Response at 24 Months | Complete Response | 0.0 Percentage of participants |
| Anastrozole | Percentage of Participants With Best Tumor Response at 24 Months | Partial Response | 6.8 Percentage of participants |
| Anastrozole | Percentage of Participants With Best Tumor Response at 24 Months | Stable Disease | 38.4 Percentage of participants |
| Anastrozole | Percentage of Participants With Best Tumor Response at 24 Months | Progressive Disease | 49.3 Percentage of participants |
Secondary
Percentage of Participants With Best Tumor Response at End of Study
Tumor Response levels were determined by the investigator and an Independent Response Evaluation Committee and Reconciled. Best Response was defined as the best response a patient achieves in the study.
Time frame: End of Study (Up to 5 years)
Population: Full Analysis Population includes all randomized participants who received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab + Anastrozole | Percentage of Participants With Best Tumor Response at End of Study | Partial Response | 21.4 Percentage of participants |
| Trastuzumab + Anastrozole | Percentage of Participants With Best Tumor Response at End of Study | Progressive Disease | 28.1 Percentage of participants |
| Trastuzumab + Anastrozole | Percentage of Participants With Best Tumor Response at End of Study | Stable Disease | 47.6 Percentage of participants |
| Trastuzumab + Anastrozole | Percentage of Participants With Best Tumor Response at End of Study | Response not assessed | 1.9 Percentage of participants |
| Trastuzumab + Anastrozole | Percentage of Participants With Best Tumor Response at End of Study | Complete Response | 1.0 Percentage of participants |
| Anastrozole | Percentage of Participants With Best Tumor Response at End of Study | Response not assessed | 4.8 Percentage of participants |
| Anastrozole | Percentage of Participants With Best Tumor Response at End of Study | Complete Response | 3.8 Percentage of participants |
| Anastrozole | Percentage of Participants With Best Tumor Response at End of Study | Partial Response | 4.8 Percentage of participants |
| Anastrozole | Percentage of Participants With Best Tumor Response at End of Study | Stable Disease | 40.4 Percentage of participants |
| Anastrozole | Percentage of Participants With Best Tumor Response at End of Study | Progressive Disease | 46.2 Percentage of participants |
Secondary
Percentage of Participants With Clinical Benefit
Clinical Benefit was defined as stable disease for ≥ six months or complete response or partial response.
Time frame: 24 Months, End of Study (Up to 5 years)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab + Anastrozole | Percentage of Participants With Clinical Benefit | 24 Months | 42.7 Percentage of participants |
| Trastuzumab + Anastrozole | Percentage of Participants With Clinical Benefit | End of Study | 45.6 Percentage of participants |
| Anastrozole | Percentage of Participants With Clinical Benefit | 24 Months | 27.9 Percentage of participants |
| Anastrozole | Percentage of Participants With Clinical Benefit | End of Study | 30.8 Percentage of participants |
Secondary
Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Final Visit Compared to Baseline
Participants rated their performance status using the ECOG Questionnaire on the following scale: 0=Fully active, perform all pre-disease activities without restriction; 1=Restricted in physically strenuous activity but ambulatory, carry out work of a light or sedentary nature; 2=Ambulatory, capable of self-care, unable to carry out any work activities, up and about more than \>50% of waking hours; 3=Capable of limited self-care, confined to bed or chair \>50% of waking hours; 4=Completely disabled, not capable of any self-care, totally confined to bed or chair; 5=Dead. The percentage of participants in the following categories: Improved: Score decrease from baseline. Unchanged: Score the same as baseline. Worse: Score increase from baseline.
Time frame: Baseline, Final Visit (Up to 24 Months)
Population: Participants from the Full Analysis Population (includes all randomized participants who received study drug) with data available for analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab + Anastrozole | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Final Visit Compared to Baseline | Improved | 10.3 Percentage of participants |
| Trastuzumab + Anastrozole | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Final Visit Compared to Baseline | No Change | 67.6 Percentage of participants |
| Trastuzumab + Anastrozole | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Final Visit Compared to Baseline | Worse | 22.1 Percentage of participants |
| Anastrozole | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Final Visit Compared to Baseline | Improved | 4.1 Percentage of participants |
| Anastrozole | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Final Visit Compared to Baseline | No Change | 64.4 Percentage of participants |
| Anastrozole | Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Final Visit Compared to Baseline | Worse | 31.5 Percentage of participants |
Secondary
Percentage of Participants With Overall Tumor Response at 24 Months
Tumor Response levels were determined by the investigator and an Independent Response Evaluation Committee and Reconciled. Overall Response was defined as either complete response or partial response.
Time frame: 24 Months
Population: Participants from the Full Analysis Population (all randomized participants who received study drug) evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab + Anastrozole | Percentage of Participants With Overall Tumor Response at 24 Months | 20.3 Percentage of participants |
| Anastrozole | Percentage of Participants With Overall Tumor Response at 24 Months | 6.8 Percentage of participants |
Secondary
Percentage of Participants With Overall Tumor Response at End of Study
Tumor Response levels were determined by the investigator and an Independent Response Evaluation Committee and Reconciled. Overall Response was defined as either complete response or partial response.
Time frame: End of Study (Up to 5 years)
Population: Participants from the Full Analysis Population (all randomized participants who received study drug) evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab + Anastrozole | Percentage of Participants With Overall Tumor Response at End of Study | 22.3 Percentage of participants |
| Anastrozole | Percentage of Participants With Overall Tumor Response at End of Study | 8.7 Percentage of participants |
Secondary
Percentage of Participants With Two-Year Survival
Time frame: 24 Months
Population: Full Analysis Population included all randomized participants who received study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab + Anastrozole | Percentage of Participants With Two-Year Survival | 52.4 Percentage of participants |
| Anastrozole | Percentage of Participants With Two-Year Survival | 45.2 Percentage of participants |
Secondary
Time to Response at 24 Months
Time to response was defined as the number of days from the day of randomization to the day complete response or partial response was first noted.
Time frame: 24 Months
Population: Participants from the Full Analysis population (all randomized participants who received study drug) evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab + Anastrozole | Time to Response at 24 Months | 2.0 Months |
| Anastrozole | Time to Response at 24 Months | 2.0 Months |
Secondary
Time to Response at End of Study
Time to response was defined as the number of days from the day of randomization to the day complete response or partial response was first noted.
Time frame: End of Study (Up to 5 years)
Population: Participants from the Full Analysis population (all randomized participants who received study drug) evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab + Anastrozole | Time to Response at End of Study | 2.4 Months |
| Anastrozole | Time to Response at End of Study | 2.1 Months |