Breast Cancer
Conditions
Keywords
Breast Cancer (BC), hormone receptor (HR), HR-positive, human epidermal growth factor receptor 2 (HER2), HER2-negative, ER-positive, advanced breast cancer (aBC), ribociclib (LEE011), premenopausal, postmenopausal
Brief summary
The purpose of the study was to evaluate the safety and efficacy of a reduced ribociclib starting dose of 400 mg in combination with a non-steroidal aromatase inhibitor (NSAI) (letrozole or anastrozole) for the treatment of pre- and postmenopausal women with hormone receptor-positive (HR-positive), HER2-negative advanced breast cancer (aBC) who have received no prior therapy for advanced disease. Premenopausal women were required to receive goserelin in both treatment arms.
Detailed description
Patients were assigned at visit Cycle 1 Day 1 to one of the following two treatment arms in a ratio of 1:1: * Experimental arm: Ribociclib 400 mg (2 × 200 mg tablets by mouth) QD on Days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28) in combination with ET consisting of: • For postmenopausal women: * Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously • For premenopausal women: * Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks. * Control arm: Ribociclib 600 mg (3 × 200 mg tablets by mouth) QD on Days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28) in combination with ET consisting of: * For postmenopausal women: \ Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously. * For premenopausal women: * Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks. Participants received study treatment until disease progression (radiologically documented according to RECIST 1.1 criteria), unacceptable toxicity, death, or discontinuation from the study treatment for any other reason. For participants who discontinued treatment for reasons other than documented disease progression, death, lost to follow-up, or withdrawal of consent, tumor assessments continued to be performed until disease progression, death, lost to follow-up, or withdrawal of consent (post-treatment efficacy follow-up).
Interventions
DRUGRibociclib
Ribociclib (at a dosage of 400 mg or 600 mg) QD orally taken on days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (days 22 to 28). Ribociclib was supplied as 200 mg tablets as individual patient supply packaged bottles.
DRUGAnastrozole
Anastrozole 1 mg tablets for oral use QD continuously
DRUGLetrozole
Letrozole 2.5 mg tablets for oral use QD continuously
DRUGGoserelin
Goserelin 3.6 mg subcutaneously once every 4 weeks (pre-menopausal women only)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria: * Patient has advanced (loco-regionally recurrent or metastatic) breast cancer not amenable to curative therapy. * Patient has a histologically and/or cytologically confirmed diagnosis of ER-positive and/or PgR-positive breast cancer based on the most recently analyzed tissue sample, and all tested by local laboratory. * Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing and based on the most recently analyzed tissue sample. * Patient must have measurable disease, i.e., at least one measurable lesion according to RECIST version 1.1. (a lesion in a previously irradiated site may only be counted as a target lesion if there is clear evidence of progression since the irradiation). * Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. * Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed by the central laboratory: * QTcF interval at screening \< 450 ms (QT interval using Fridericia's correction) * Mean resting heart rate 50 to 90 bpm (determined from the ECG) * Women of childbearing potential (CBP), defined as all women physiologically capable of becoming pregnant, must have confirmed negative serum pregnancy test (for β-hCG) within 14 days prior to randomization. * Women of CBP must be willing to use highly effective methods of contraception. Key
Exclusion criteria
* Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's judgment. * Patient who received any prior systemic anti-cancer therapy(including endocrine therapy, chemotherapy, prior CDK4/6 inhibitors) for aBC. Patients who received neo-/adjuvant therapy for breast cancer are eligible. * Patient is concurrently using other anti-cancer therapy. * Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major toxicities. * Patient has received extended-field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to randomization, and has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion). Patients in whom ≥ * 25% of the bone marrow has been previously irradiated are also excluded. * Patient has a concurrent malignancy or malignancy within 3 years of the randomization date, with the exception of adequately treated basal or squamous cell skin carcinoma, or curatively resected cervical carcinoma in situ. * Patients with central nervous system (CNS) involvement unless they meet specific stability criteria. * Patient has clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality. * Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, and has not fully recovered from side effects of such treatment. Other protocol-defined Inclusion/Exclusion may apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to 23.8 months | ORR defined as the percentage of participants with best overall response (BOR) of confirmed complete response (CR) or partial response (PR) assessed by local investigators according to RECIST 1.1. CR: Disappearance of all lesions with lymph nodes measuring \< 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to approximately 60 months | Progression free survival (PFS) was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause. PFS was censored if no PFS event was observed. The censoring date was the date of the last adequate tumor assessment. Clinical deterioration without objective radiological evidence was not considered as documented disease progression. PFS was assessed via a local radiology assessment as well as Blinded Independent Review Committee (BIRC) according to RECIST 1.1. |
| Clinical Benefit Rate (CBR) | Up to approximately 60 months | Clinical benefit rate (CBR) was defined as the proportion of patients with a best overall response of complete response (CR), or partial response (PR), or an overall response of stable disease (SD), lasting for at least 24 weeks. CR, PR, and SD were defined as per local review as well as Blinded Independent Review Committee (BIRC) according to RECIST 1.1. A patient was considered to have SD for 24 weeks or longer if a SD response was recorded at 24-1=23 weeks or later from randomization, allowing for the ±1 week visit window for tumor assessments. CR: Disappearance of all lesions with lymph nodes measuring \< 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) | Up to approximately 60 months | Time to response (TTR) was defined as the time from the date of randomization to the first documented response of either complete response (CR) or partial response (PR), which had to be subsequently confirmed (although the date of initial response was used, not the date of confirmation). CR and PR were based on tumor response data as per local review and according to RECIST 1.1. CR: Disappearance of all lesions with lymph nodes measuring \< 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. |
| Change From Baseline in QTc (With Fridericia's Correction) at Cycle 1 Day 15 (at 2 Hours Post-dose) | Baseline and Cycle 1 Day 15 at 2 hours post-dose. Cycle = 28 days | Electrocardiogram (ECG) data was collected via 12-lead digital ECG machines. Change from baseline in the QT interval (a segment of the ECG that reflects the time it takes for the heart to repolarize after each heartbeat) was corrected for heart rate using Fridericia's formula (ΔQTcF). |
| Pharmacokinetics (PK) of Ribociclib: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days | PK parameters were calculated by non-compartmental analysis. Cmax is the maximum observed plasma drug concentration after single dose administration. |
| PK of Ribociclib: Time to Reach Observed Maximum Concentration (Tmax) | Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days | PK parameters were calculated by non-compartmental analysis. Tmax is the time to reach maximum observed plasma concentration. Actual recorded sampling times were considered for the calculations. |
| PK of Ribociclib: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) | Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days | PK parameters were calculated by non-compartmental analysis. AUC0-24 is the area under the plasma concentration-time curve from 0 to 24 hours |
| Duration of Response (DOR) | Up to approximately 60 months | Duration of response (DOR) only applied to patients whose best overall response was complete response (CR) or partial response (PR) according to RECIST 1.1 based on tumor response data per local review. The start date was the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date was defined as the date of the first documented progression or death due to underlying cancer. Patients continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. CR: Disappearance of all lesions with lymph nodes measuring \< 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
Argentina, Austria, Belgium, Brazil, Bulgaria, Canada, Colombia, Costa Rica, Czechia, Finland, France, Germany, Hungary, India, Jordan, Lithuania, Peru, Portugal, Russia, South Africa, Sweden, Thailand, United States
Participant flow
Recruitment details
Participants were enrolled in 90 centers across 23 countries.
Pre-assignment details
A total of 558 subjects were screened of which 376 participants were randomized on a 1:1 basis.
Participants by arm
| Arm | Count |
|---|---|
| Ribociclib 400 mg Ribociclib 400 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+goserelin in premenopausal women) | 188 |
| Ribociclib 600 mg Ribociclib 600 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+ goserelin in premenopausal women) | 188 |
| Total | 376 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Post-treatment Efficacy Follow-up | Adverse Event | 1 | 0 |
| Post-treatment Efficacy Follow-up | Death | 1 | 0 |
| Post-treatment Efficacy Follow-up | Lost to Follow-up | 1 | 0 |
| Post-treatment Efficacy Follow-up | Physician Decision | 1 | 2 |
| Post-treatment Efficacy Follow-up | Progressive disease | 11 | 14 |
| Post-treatment Efficacy Follow-up | Sponsor decision | 3 | 7 |
| Post-treatment Efficacy Follow-up | Withdrawal by Subject | 4 | 3 |
| Treatment Period | Adverse Event | 21 | 24 |
| Treatment Period | Death | 2 | 3 |
| Treatment Period | Lost to Follow-up | 1 | 1 |
| Treatment Period | Physician Decision | 9 | 7 |
| Treatment Period | Progressive disease | 98 | 94 |
| Treatment Period | Protocol Violation | 2 | 1 |
| Treatment Period | Sponsor decision | 46 | 53 |
| Treatment Period | Withdrawal by Subject | 9 | 5 |
Baseline characteristics
| Characteristic | Ribociclib 600 mg | Ribociclib 400 mg | Total |
|---|---|---|---|
| Age, Continuous | 57.0 Years STANDARD_DEVIATION 12.37 | 58.7 Years STANDARD_DEVIATION 12.96 | 57.9 Years STANDARD_DEVIATION 12.68 |
| Race/Ethnicity, Customized Asian | 9 Participants | 13 Participants | 22 Participants |
| Race/Ethnicity, Customized Black | 12 Participants | 5 Participants | 17 Participants |
| Race/Ethnicity, Customized Caucasian | 143 Participants | 147 Participants | 290 Participants |
| Race/Ethnicity, Customized Native American or Alaska Native | 10 Participants | 14 Participants | 24 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Unknown | 10 Participants | 8 Participants | 18 Participants |
| Sex: Female, Male Female | 188 Participants | 188 Participants | 376 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 | 5 / 188 | 6 / 188 | 3 / 22 | 2 / 26 |
| other Total, other adverse events | 175 / 188 | 178 / 188 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 38 / 188 | 37 / 188 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR defined as the percentage of participants with best overall response (BOR) of confirmed complete response (CR) or partial response (PR) assessed by local investigators according to RECIST 1.1. CR: Disappearance of all lesions with lymph nodes measuring \< 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 23.8 months
Population: The Full Analysis Set (FAS) including all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribociclib 400 mg | Overall Response Rate (ORR) | 41.5 Percentage of participants |
| Ribociclib 600 mg | Overall Response Rate (ORR) | 45.3 Percentage of participants |
Secondary
Change From Baseline in QTc (With Fridericia's Correction) at Cycle 1 Day 15 (at 2 Hours Post-dose)
Electrocardiogram (ECG) data was collected via 12-lead digital ECG machines. Change from baseline in the QT interval (a segment of the ECG that reflects the time it takes for the heart to repolarize after each heartbeat) was corrected for heart rate using Fridericia's formula (ΔQTcF).
Time frame: Baseline and Cycle 1 Day 15 at 2 hours post-dose. Cycle = 28 days
Population: Participants who received at least one dose of study treatment and had available QT assessments conducted at both baseline and Cycle 1 Day 15 (2 hours post-dose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ribociclib 400 mg | Change From Baseline in QTc (With Fridericia's Correction) at Cycle 1 Day 15 (at 2 Hours Post-dose) | 12.5 milliseconds | Standard Deviation 12.91 |
| Ribociclib 600 mg | Change From Baseline in QTc (With Fridericia's Correction) at Cycle 1 Day 15 (at 2 Hours Post-dose) | 19.7 milliseconds | Standard Deviation 18.5 |
Secondary
Clinical Benefit Rate (CBR)
Clinical benefit rate (CBR) was defined as the proportion of patients with a best overall response of complete response (CR), or partial response (PR), or an overall response of stable disease (SD), lasting for at least 24 weeks. CR, PR, and SD were defined as per local review as well as Blinded Independent Review Committee (BIRC) according to RECIST 1.1. A patient was considered to have SD for 24 weeks or longer if a SD response was recorded at 24-1=23 weeks or later from randomization, allowing for the ±1 week visit window for tumor assessments. CR: Disappearance of all lesions with lymph nodes measuring \< 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 60 months
Population: The Full Analysis Set (FAS) including all randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ribociclib 400 mg | Clinical Benefit Rate (CBR) | 142 Participants |
| Ribociclib 600 mg | Clinical Benefit Rate (CBR) | 133 Participants |
Secondary
Duration of Response (DOR)
Duration of response (DOR) only applied to patients whose best overall response was complete response (CR) or partial response (PR) according to RECIST 1.1 based on tumor response data per local review. The start date was the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date was defined as the date of the first documented progression or death due to underlying cancer. Patients continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. CR: Disappearance of all lesions with lymph nodes measuring \< 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 60 months
Population: Full Analysis Set (FAS) - Only responders included
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib 400 mg | Duration of Response (DOR) | 26.5 Months |
| Ribociclib 600 mg | Duration of Response (DOR) | 28.8 Months |
Secondary
Pharmacokinetics (PK) of Ribociclib: Maximum Observed Plasma Concentration (Cmax)
PK parameters were calculated by non-compartmental analysis. Cmax is the maximum observed plasma drug concentration after single dose administration.
Time frame: Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days
Population: Participants who provided an evaluable PK parameter (Cmax) and received at least 10 consecutive daily ribociclib doses of 400 mg or 600 mg immediately prior to and on the PK collection day
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ribociclib 400 mg | Pharmacokinetics (PK) of Ribociclib: Maximum Observed Plasma Concentration (Cmax) | 1240 nanogram / milliliter (ng / mL) | Standard Deviation 739 |
| Ribociclib 600 mg | Pharmacokinetics (PK) of Ribociclib: Maximum Observed Plasma Concentration (Cmax) | 1740 nanogram / milliliter (ng / mL) | Standard Deviation 918 |
Secondary
PK of Ribociclib: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24)
PK parameters were calculated by non-compartmental analysis. AUC0-24 is the area under the plasma concentration-time curve from 0 to 24 hours
Time frame: Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days
Population: Participants who provided an evaluable PK parameter (AUC0-24) and received at least 10 consecutive daily ribociclib doses of 400 mg or 600 mg immediately prior to and on the PK collection day
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ribociclib 400 mg | PK of Ribociclib: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) | 18700 ng x h / mL | Standard Deviation 11600 |
| Ribociclib 600 mg | PK of Ribociclib: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) | 31600 ng x h / mL | Standard Deviation 14300 |
Secondary
PK of Ribociclib: Time to Reach Observed Maximum Concentration (Tmax)
PK parameters were calculated by non-compartmental analysis. Tmax is the time to reach maximum observed plasma concentration. Actual recorded sampling times were considered for the calculations.
Time frame: Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days
Population: Participants who provided an evaluable PK parameter (Tmax) and received at least 10 consecutive daily ribociclib doses of 400 mg or 600 mg immediately prior to and on the PK collection day
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib 400 mg | PK of Ribociclib: Time to Reach Observed Maximum Concentration (Tmax) | 2.08 hours (h) |
| Ribociclib 600 mg | PK of Ribociclib: Time to Reach Observed Maximum Concentration (Tmax) | 4.00 hours (h) |
Secondary
Progression-free Survival (PFS)
Progression free survival (PFS) was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause. PFS was censored if no PFS event was observed. The censoring date was the date of the last adequate tumor assessment. Clinical deterioration without objective radiological evidence was not considered as documented disease progression. PFS was assessed via a local radiology assessment as well as Blinded Independent Review Committee (BIRC) according to RECIST 1.1.
Time frame: Up to approximately 60 months
Population: The Full Analysis Set (FAS) including all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib 400 mg | Progression-free Survival (PFS) | 26.9 Months |
| Ribociclib 600 mg | Progression-free Survival (PFS) | 25.1 Months |
Secondary
Time to Response (TTR)
Time to response (TTR) was defined as the time from the date of randomization to the first documented response of either complete response (CR) or partial response (PR), which had to be subsequently confirmed (although the date of initial response was used, not the date of confirmation). CR and PR were based on tumor response data as per local review and according to RECIST 1.1. CR: Disappearance of all lesions with lymph nodes measuring \< 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 60 months
Population: Full Analysis Set (FAS) - Only responders included
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib 400 mg | Time to Response (TTR) | 13.1 Months |
| Ribociclib 600 mg | Time to Response (TTR) | 9.0 Months |