Advanced Breast Cancer
Conditions
Keywords
HR-positive, HER2-negative, Advanced breast cancer, LEE011, ribociclib, fulvestrant, faslodex, CDK, CDK4, CDK6, CDK4/6, CDK4/6 inhibitor, Phase III, ER-positive, PR-positive, Postmenopausal, Men, Breast Neoplasms, Breast Diseases, Neoplasms, Neoplasms by Site, Antineoplastic Agents, Antineoplastic Agents, Hormonal, Estrogen Receptor Antagonists, Hormone Antagonists, Hormones, Hormone Substitutes, and Hormone Antagonists, Molecular Mechanisms of Pharmacological Action, Pharmacologic Actions, Therapeutic Use
Brief summary
The main aim of this study was to evaluate the efficacy and safety of adding ribociclib to fulvestrant in men and postmenopausal women with hormone receptor positive (HR+), HER2-negative advanced breast cancer.
Detailed description
This study was a randomized, phase III, double-blind, placebo-controlled international trial aimed at determining the efficacy and safety of treatment with fulvestrant in combination with ribociclib compared to fulvestrant with placebo in men and postmenopausal women diagnosed with HR+, HER2-negative advanced breast cancer. The study comprised four phases: screening (up to 28 days), randomized treatment, post-treatment disease progression follow-up, and post-treatment survival follow-up. Enrolled participants were randomly assigned to receive either fulvestrant+ribociclib or fulvestrant+placebo in a ratio of 2:1. The randomization process was stratified based on the presence of liver and/or lung metastases (yes versus no) and prior endocrine therapy. Treatment was administered until disease progression, occurrence of unacceptable toxicity, or discontinuation from the study treatment for other reasons. Participants who discontinued treatment due to reasons other than disease progression or withdrawal of consent for efficacy follow-up continued to be monitored until disease progression, death, withdrawal of consent, loss to follow-up, or subject/guardian decision. All participants who discontinued treatment were followed for survival until the predetermined number of overall survival (OS) events was reached. A protocol amendment 4 (dated 29-Jan-2020) allowed for unblinding of study participants, and those still receiving placebo had the option to switch to the ribociclib arm. The decision for crossover was made at the investigator's discretion and required patient consent.
Interventions
DRUGRibociclib
Ribociclib capsules were administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle.
DRUGFulvestrant
Fulvestrant was administered via intramuscular injections at a dose of 500mg every 28 days, starting on Day 1 of each cycle. In Cycle 1, an additional dose of Fulvestrant was given on Day 15.
DRUGPlacebo
Placebo capsules were administered orally for 21 consecutive days within a 28-day cycle.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Following protocol amendment 4 (29-Jan-2020), study participants were unblinded, with an opportunity for those patients still in the study in the arm of placebo + fulvestrant to transition to the treatment of ribociclib + fulvestrant.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Patients were adults, both male and female, aged ≥ 18 years at the time of providing informed consent. Female patients were required to be postmenopausal. Informed consent was obtained prior to any trial-related activities, following local guidelines. 2. Patients had a confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer, determined through histological and/or cytological examination by a local laboratory. Patients also had HER2-negative breast cancer. 3. Patients had either measurable disease as per RECIST 1.1 criteria or at least one predominantly lytic bone lesion. 4. Patients had advanced breast cancer, which included locoregionally recurrent disease not amenable to curative therapies (such as surgery or radiotherapy) or metastatic breast cancer. Patients fell into one of the following categories: * Newly diagnosed with advanced/metastatic breast cancer and treatment-naïve. * Relapsed with documented evidence of relapse more than 12 months after completing (neo)adjuvant endocrine therapy, without any prior treatment for advanced/metastatic disease. * Relapsed with documented evidence of relapse on or within 12 months from completing (neo)adjuvant endocrine therapy, without any prior treatment for advanced/metastatic disease. * Relapsed with documented evidence of relapse more than 12 months after completing adjuvant endocrine therapy and subsequently progressed after receiving one line of endocrine therapy (antiestrogen or aromatase inhibitor) for advanced/metastatic disease. * Newly diagnosed with advanced/metastatic breast cancer at diagnosis and progressed after receiving one line of endocrine therapy (antiestrogen or aromatase inhibitor), with documented evidence of progression. 5. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Patients had adequate bone marrow and organ function. Key
Exclusion criteria
Patients with symptomatic visceral disease or disease burden that rendered them ineligible for endocrine therapy, based on the investigator's judgment. 2\. Patients who had received prior treatment with chemotherapy (except for neoadjuvant/adjuvant chemotherapy), fulvestrant, or any CDK4/6 inhibitor. 3\. Patients with inflammatory breast cancer at the screening stage. 4. Patients with central nervous system (CNS) involvement, unless they were at least 4 weeks from completing prior therapy before initiating the study treatment and had a stable CNS tumor at the time of screening. They were also required not to be receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases. 5\. Patients with clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality. 6\. Patients who were currently receiving any of the following substances, which could not be discontinued 7 days prior to initiating treatment: * Known strong inducers or inhibitors of CYP3A4/5. * Substances with a known risk of prolonging the QT interval or inducing Torsades de Pointes. * Substances with a narrow therapeutic window and predominantly metabolized through CYP3A4/5. * Herbal preparations/medications, dietary supplements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per Investigator Assessment | From randomization to first documented progression or death, assessed up to approximately 26 months | PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. In cases where patients did not experience an event, the PFS was censored at 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 local radiology assessment according to RECIST 1.1. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group. The distribution of PFS between the two arms was compared using a stratified log-rank test at a one-sided 2.5% level of significance. The PFS hazard ratio with two-sided 95% confidence interval was derived from the stratified Cox proportional hazards model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC) | From randomization to first documented progression or death, assessed up to approximately 26 months | PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. In cases where patients did not experience an event, the PFS was censored at 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 BIRC assessment according to RECIST 1.1. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group. |
| Overall Response Rate (ORR) Per Investigator Assessment | Up to approximately 26 months | ORR was defined as the percentage of participants with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 as per investigator 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. |
| Clinical Benefit Rate (CBR) Per Investigator Assessment | Up to approximately 26 months | CBR was defined as the percentage of participants with a best overall response of CR or PR or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1 as per investigator 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. 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) Per Investigator Assessment | From randomization to first response, assessed up to approximately 26 months | TTR was defined as the time from randomization to the first documented and confirmed response (CR or PR) as defined by RECIST 1.1 per investigator assessment. The Kaplan-Meier method was used to estimate TTR, and the median TTR, along with 95% confidence intervals, was reported for each treatment group. Participants who did not achieve a confirmed response were censored at the maximum follow-up time for patients who had a PFS event (i.e. either progressed or died due to any cause) or at the date of last adequate tumor assessment otherwise. 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. |
| Duration of Response (DOR) Per Investigator Assessment | From first documented response to progression or death, assessed up to approximately 26 months | DOR was defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer as defined in RECIST 1.1 per investigator assessment. The Kaplan-Meier method was used to estimate DOR, and the median DOR, along with 95% confidence intervals, was reported for each treatment group. If a participant had not had an event, duration was censored at the date of 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. |
| Overall Survival (OS) | From randomization to death, assessed up to approximately 46 months | OS was defined as the time from the date of randomization to the date of death from any cause. In cases where the patient's death was not recorded, the OS value was censored at the date of the last known patient's survival status. As per protocol, the final OS analysis was conducted after approximately 351 deaths were documented. OS was estimated using the Kaplan-Meier method. The median OS, along with 95% confidence intervals (CIs), was reported for each treatment group. The distribution of OS between the two treatment arms was compared using a log-rank test at one-sided cumulative 2.5% level of significance. A stratified Cox regression was used to estimate the OS hazard ratio and the associated 95% CI. |
| Time to Definitive 10% Deterioration in the Global Health Status/Quality of Life (GHS/QoL) Scale Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30) | Up to approximately 26 months | The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, a GHS/QoL scale, and 6 single items. GHS/QoL scale scores range between 0 and 100. A high score for GHS/QoL represents better functioning or QoL. The time to definitive 10% deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10% relative to baseline worsening of the QoL score (without further improvement above the threshold) or death due to any cause. The Kaplan-Meier method was used to estimate the distribution, and the median time to definitive 10% deterioration, along with 95% confidence intervals, was reported for each treatment group. If a patient had not had an event, time to deterioration was censored at the date of the last adequate QoL evaluation. |
| Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Baseline, every 8 weeks after randomization during 18 months, then every 12 weeks up to end of treatment; end of treatment; and every 8 or 12 weeks post-treatment until progression (post-treatment efficacy visits), assessed up to approximately 26 months | The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, a GHS/QoL scale, and 6 single items. GHS/QoL scale scores range between 0 and 100. A high score for GHS/QoL represents better functioning or QoL. The change from baseline in the GHS/QoL score was assessed. A positive change from baseline indicates improvement. For subjects who discontinued treatment without disease progression, post-treatment efficacy visits occurred every 8 weeks during the initial 18 months since start of treatment, followed by visits every 12 weeks until disease progression. |
| Ribociclib Plasma Concentrations | Cycle 1 and Cycle 2 at Day 15 pre-dose and at 2, 4, and 6 hours post-dose. Cycle=28 days | Blood samples were collected to assess the concentration by time point for ribociclib. Participants were classified into the following dose groups at each timepoint: 1) ribociclib 600 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 600 mg immediately prior to the blood collection without a dose change or interruption. 2) ribociclib 400 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 400 mg immediately prior to the blood collection without a dose change or interruption. 3) ribociclib 200 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 200 mg immediately prior to the blood collection without a dose change or interruption. |
| LEQ803 Plasma Concentrations | Cycle 1 and Cycle 2 at Day 15 pre-dose and at 2, 4, and 6 hours post-dose. Cycle = 28 days | Blood samples were collected to assess the concentration by time point for LEQ803, a metabolite of ribociclib. Participants were classified into the following dose groups at each timepoint: 1) ribociclib 600 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 600 mg immediately prior to the blood collection without a dose change or interruption. 2) ribociclib 400 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 400 mg immediately prior to the blood collection without a dose change or interruption. 3) ribociclib 200 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 200 mg immediately prior to the blood collection without a dose change or interruption. |
| Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) in One Score Category | Up to approximately 26 months | ECOG PS categorized patients based on their ability to perform daily activities and self-care, with scores ranging from 0 to 5. A score of 0 indicated no restrictions in activity, while higher scores indicated increasing limitations. Time to definitive deterioration was defined as the time from the date of randomization to the date of the event, defined as experiencing an increase in ECOG PS by at least one category from the baseline or death. A deterioration was considered definitive if no improvements in the ECOG PS were observed at a subsequent time. The Kaplan-Meier method was used to estimate the distribution, and the median time to definitive deterioration, along with 95% confidence intervals, was reported for each treatment group. Patients receiving any further therapy prior to definitive worsening were censored at their date of last assessment prior to start of therapy. Patients that had not worsened at the data cutoff point were censored at the date of last assessment. |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Colombia, Czechia, Denmark, France, Germany, Hungary, Italy, Jordan, Lebanon, Malaysia, Mexico, Netherlands, Norway, Poland, Portugal, Russia, Singapore, South Korea, Spain, Sweden, Switzerland, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
174 sites across 30 countries enrolled participants
Pre-assignment details
Screening assessments were conducted up to 28 days prior to the randomization
Participants by arm
| Arm | Count |
|---|---|
| Ribociclib + Fulvestrant Ribociclib was administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. | 484 |
| Placebo + Fulvestrant Placebo was administered orally for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. Participants were unblinded after the implementation of protocol amendment 4 (29-Jan-20) and were given the option to crossover to treatment with ribociclib and fulvestrant. | 242 |
| Total | 726 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Post-treatment Efficacy Follow-up | Adverse Event | 1 | 0 |
| Post-treatment Efficacy Follow-up | Death | 2 | 1 |
| Post-treatment Efficacy Follow-up | Physician Decision | 0 | 1 |
| Post-treatment Efficacy Follow-up | Progressive disease | 23 | 6 |
| Post-treatment Efficacy Follow-up | Study Terminated as per protocol | 2 | 0 |
| Post-treatment Efficacy Follow-up | Subject/Guardian Decision | 6 | 1 |
| Treatment Period | Adverse Event | 51 | 9 |
| Treatment Period | Death | 2 | 1 |
| Treatment Period | Physician Decision | 32 | 8 |
| Treatment Period | Progressive disease | 314 | 200 |
| Treatment Period | Protocol deviation | 1 | 1 |
| Treatment Period | Study terminated as per protocol | 46 | 14 |
| Treatment Period | Subject/guardian decision | 38 | 8 |
| Treatment Period | Technical problems | 0 | 1 |
Baseline characteristics
| Characteristic | Ribociclib + Fulvestrant | Placebo + Fulvestrant | Total |
|---|---|---|---|
| Age, Continuous | 63.4 Years STANDARD_DEVIATION 9.78 | 62.8 Years STANDARD_DEVIATION 10.59 | 63.2 Years STANDARD_DEVIATION 10.05 |
| Race/Ethnicity, Customized Asian | 45 Participants | 18 Participants | 63 Participants |
| Race/Ethnicity, Customized Black | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Caucasian | 406 Participants | 213 Participants | 619 Participants |
| Race/Ethnicity, Customized Native American | 5 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Other | 10 Participants | 3 Participants | 13 Participants |
| Race/Ethnicity, Customized Unkown | 15 Participants | 5 Participants | 20 Participants |
| Sex: Female, Male Female | 484 Participants | 242 Participants | 726 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 | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 13 / 483 | 264 / 380 | 8 / 241 | 153 / 210 | 0 / 3 | 1 / 1 |
| other Total, other adverse events | 475 / 483 | 0 / 0 | 225 / 241 | 0 / 0 | 3 / 3 | 0 / 0 |
| serious Total, serious adverse events | 179 / 483 | 0 / 0 | 51 / 241 | 0 / 0 | 1 / 3 | 0 / 0 |
Outcome results
Primary
Progression Free Survival (PFS) Per Investigator Assessment
PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. In cases where patients did not experience an event, the PFS was censored at 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 local radiology assessment according to RECIST 1.1. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group. The distribution of PFS between the two arms was compared using a stratified log-rank test at a one-sided 2.5% level of significance. The PFS hazard ratio with two-sided 95% confidence interval was derived from the stratified Cox proportional hazards model.
Time frame: From randomization to first documented progression or death, assessed up to approximately 26 months
Population: The Full Analysis Set (FAS) including all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + Fulvestrant | Progression Free Survival (PFS) Per Investigator Assessment | 20.5 Months |
| Placebo + Fulvestrant | Progression Free Survival (PFS) Per Investigator Assessment | 12.8 Months |
p-value: 4.1e-795% CI: [0.48, 0.732]Log Rank
Secondary
Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30
The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, a GHS/QoL scale, and 6 single items. GHS/QoL scale scores range between 0 and 100. A high score for GHS/QoL represents better functioning or QoL. The change from baseline in the GHS/QoL score was assessed. A positive change from baseline indicates improvement. For subjects who discontinued treatment without disease progression, post-treatment efficacy visits occurred every 8 weeks during the initial 18 months since start of treatment, followed by visits every 12 weeks until disease progression.
Time frame: Baseline, every 8 weeks after randomization during 18 months, then every 12 weeks up to end of treatment; end of treatment; and every 8 or 12 weeks post-treatment until progression (post-treatment efficacy visits), assessed up to approximately 26 months
Population: Randomized participants with data available at the specified time points. Number analyzed refers to the number of participants with an evaluable value at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 3 Day 1 (Cycle= 28 days) | 4.5 Score on a Scale | Standard Deviation 18.53 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 15 Day 1 (Cycle= 28 days) | 3.6 Score on a Scale | Standard Deviation 18.34 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 17 Day 1 (Cycle= 28 days) | 3.9 Score on a Scale | Standard Deviation 20.31 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 19 Day 1 (Cycle= 28 days) | 3.8 Score on a Scale | Standard Deviation 17.57 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT9 | 8.3 Score on a Scale | Standard Deviation 46.4 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 22 Day 1 (Cycle= 28 days) | 6.6 Score on a Scale | Standard Deviation 20.78 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 25 Day 1 (Cycle= 28 days) | 5.7 Score on a Scale | Standard Deviation 16.81 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 28 Day 1 (Cycle= 28 days) | 12.5 Score on a Scale | Standard Deviation 16.48 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | End of treatment (EOT) | -5.2 Score on a Scale | Standard Deviation 25.84 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT1 | 4.5 Score on a Scale | Standard Deviation 21.2 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT2 | -4.8 Score on a Scale | Standard Deviation 19.75 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT3 | 14.6 Score on a Scale | Standard Deviation 24.88 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT4 | 10.0 Score on a Scale | Standard Deviation 20.75 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT5 | 13.9 Score on a Scale | Standard Deviation 20.97 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT6 | 22.2 Score on a Scale | Standard Deviation 12.73 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT7 | 19.4 Score on a Scale | Standard Deviation 20.97 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT8 | 37.5 Score on a Scale | Standard Deviation 17.68 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT10 | -8.3 Score on a Scale | — |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 5 Day 1 (Cycle= 28 days) | 4.2 Score on a Scale | Standard Deviation 19.97 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 7 Day 1 (Cycle= 28 days) | 4.9 Score on a Scale | Standard Deviation 19.47 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 9 Day 1 (Cycle= 28 days) | 4.1 Score on a Scale | Standard Deviation 19.36 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 11 Day 1 (Cycle= 28 days) | 4.9 Score on a Scale | Standard Deviation 17.57 |
| Ribociclib + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 13 Day 1 (Cycle= 28 days) | 4.4 Score on a Scale | Standard Deviation 18.53 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 3 Day 1 (Cycle= 28 days) | 2.7 Score on a Scale | Standard Deviation 17.5 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | End of treatment (EOT) | -5.5 Score on a Scale | Standard Deviation 24.54 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 5 Day 1 (Cycle= 28 days) | 3.2 Score on a Scale | Standard Deviation 18.09 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT4 | -25.0 Score on a Scale | — |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 7 Day 1 (Cycle= 28 days) | 4.3 Score on a Scale | Standard Deviation 17.3 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 22 Day 1 (Cycle= 28 days) | 4.7 Score on a Scale | Standard Deviation 17 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 9 Day 1 (Cycle= 28 days) | 3.3 Score on a Scale | Standard Deviation 17.61 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT1 | -33.3 Score on a Scale | Standard Deviation 23.57 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 11 Day 1 (Cycle= 28 days) | 2.3 Score on a Scale | Standard Deviation 18.21 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 25 Day 1 (Cycle= 28 days) | 8.3 Score on a Scale | Standard Deviation 18.22 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 13 Day 1 (Cycle= 28 days) | 1.3 Score on a Scale | Standard Deviation 19.48 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT3 | -16.7 Score on a Scale | Standard Deviation 0 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 15 Day 1 (Cycle= 28 days) | 3.6 Score on a Scale | Standard Deviation 19.86 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 28 Day 1 (Cycle= 28 days) | 19.4 Score on a Scale | Standard Deviation 12.73 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 17 Day 1 (Cycle= 28 days) | 3.4 Score on a Scale | Standard Deviation 21.61 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post EOT2 | -16.7 Score on a Scale | Standard Deviation 23.57 |
| Placebo + Fulvestrant | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 19 Day 1 (Cycle= 28 days) | 3.7 Score on a Scale | Standard Deviation 18.52 |
Secondary
Clinical Benefit Rate (CBR) Per Investigator Assessment
CBR was defined as the percentage of participants with a best overall response of CR or PR or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1 as per investigator 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. 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 26 months
Population: FAS including all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribociclib + Fulvestrant | Clinical Benefit Rate (CBR) Per Investigator Assessment | 70.2 Percentage of participants |
| Placebo + Fulvestrant | Clinical Benefit Rate (CBR) Per Investigator Assessment | 62.8 Percentage of participants |
Secondary
Duration of Response (DOR) Per Investigator Assessment
DOR was defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer as defined in RECIST 1.1 per investigator assessment. The Kaplan-Meier method was used to estimate DOR, and the median DOR, along with 95% confidence intervals, was reported for each treatment group. If a participant had not had an event, duration was censored at the date of 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: From first documented response to progression or death, assessed up to approximately 26 months
Population: Randomized participants with confirmed CR or PR as per investigator assessment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + Fulvestrant | Duration of Response (DOR) Per Investigator Assessment | NA Months |
| Placebo + Fulvestrant | Duration of Response (DOR) Per Investigator Assessment | NA Months |
Secondary
LEQ803 Plasma Concentrations
Blood samples were collected to assess the concentration by time point for LEQ803, a metabolite of ribociclib. Participants were classified into the following dose groups at each timepoint: 1) ribociclib 600 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 600 mg immediately prior to the blood collection without a dose change or interruption. 2) ribociclib 400 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 400 mg immediately prior to the blood collection without a dose change or interruption. 3) ribociclib 200 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 200 mg immediately prior to the blood collection without a dose change or interruption.
Time frame: Cycle 1 and Cycle 2 at Day 15 pre-dose and at 2, 4, and 6 hours post-dose. Cycle = 28 days
Population: All participants with at least one evaluable ribociclib concentration. Number analyzed indicated the number of participants with an evaluable ribociclib concentration at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 1 Day 15 predose (ribociclib 600 mg) | 75.6 ng/mL | Geometric Coefficient of Variation 50.4 |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 1 Day 15 2 hours post-dose (ribociclib 600 mg) | 134 ng/mL | Geometric Coefficient of Variation 44.5 |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 1 Day 15 4 hours post-dose (ribociclib 600 mg) | 137 ng/mL | Geometric Coefficient of Variation 42 |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 1 Day 15 6 hours post-dose (ribociclib 600 mg) | 128 ng/mL | Geometric Coefficient of Variation 42.4 |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 2 Day 15 predose (ribociclib 600 mg) | 72.7 ng/mL | Geometric Coefficient of Variation 62.9 |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 2 Day 15 predose (ribociclib 400 mg) | 46.2 ng/mL | Geometric Coefficient of Variation 52.3 |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 2 Day 15 2 hours post-dose (ribociclib 600 mg) | 126 ng/mL | Geometric Coefficient of Variation 56.4 |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 2 Day 15 2 hours post-dose (ribociclib 400 mg) | 70.8 ng/mL | Geometric Coefficient of Variation 68.5 |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 2 Day 15 2 hours post-dose (ribociclib 200 mg) | 36.0 ng/mL | — |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 2 Day 15 4 hours post-dose (ribociclib 600 mg) | 134 ng/mL | Geometric Coefficient of Variation 44.9 |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 2 Day 15 4 hours post-dose (ribociclib 400 mg) | 79.3 ng/mL | Geometric Coefficient of Variation 67.2 |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 2 Day 15 4 hours post-dose (ribociclib 200 mg) | 41.9 ng/mL | — |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 2 Day 15 6 hours post-dose (ribociclib 600 mg) | 122 ng/mL | Geometric Coefficient of Variation 60.1 |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 2 Day 15 6 hours post-dose (ribociclib 400 mg) | 72.3 ng/mL | Geometric Coefficient of Variation 75.4 |
| Ribociclib + Fulvestrant | LEQ803 Plasma Concentrations | Cycle 2 Day 15 6 hours post-dose (ribociclib 200 mg) | 38.3 ng/mL | — |
Secondary
Overall Response Rate (ORR) Per Investigator Assessment
ORR was defined as the percentage of participants with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 as per investigator 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 26 months
Population: FAS including all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribociclib + Fulvestrant | Overall Response Rate (ORR) Per Investigator Assessment | 32.4 Percentage of participants |
| Placebo + Fulvestrant | Overall Response Rate (ORR) Per Investigator Assessment | 21.5 Percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of randomization to the date of death from any cause. In cases where the patient's death was not recorded, the OS value was censored at the date of the last known patient's survival status. As per protocol, the final OS analysis was conducted after approximately 351 deaths were documented. OS was estimated using the Kaplan-Meier method. The median OS, along with 95% confidence intervals (CIs), was reported for each treatment group. The distribution of OS between the two treatment arms was compared using a log-rank test at one-sided cumulative 2.5% level of significance. A stratified Cox regression was used to estimate the OS hazard ratio and the associated 95% CI.
Time frame: From randomization to death, assessed up to approximately 46 months
Population: FAS including all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + Fulvestrant | Overall Survival (OS) | NA Months |
| Placebo + Fulvestrant | Overall Survival (OS) | 40.0 Months |
p-value: 0.0045595% CI: [0.568, 0.924]Log Rank
Secondary
Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC)
PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. In cases where patients did not experience an event, the PFS was censored at 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 BIRC assessment according to RECIST 1.1. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group.
Time frame: From randomization to first documented progression or death, assessed up to approximately 26 months
Population: FAS including all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + Fulvestrant | Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC) | NA Months |
| Placebo + Fulvestrant | Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC) | 10.9 Months |
95% CI: [0.345, 0.703]
Secondary
Ribociclib Plasma Concentrations
Blood samples were collected to assess the concentration by time point for ribociclib. Participants were classified into the following dose groups at each timepoint: 1) ribociclib 600 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 600 mg immediately prior to the blood collection without a dose change or interruption. 2) ribociclib 400 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 400 mg immediately prior to the blood collection without a dose change or interruption. 3) ribociclib 200 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 200 mg immediately prior to the blood collection without a dose change or interruption.
Time frame: Cycle 1 and Cycle 2 at Day 15 pre-dose and at 2, 4, and 6 hours post-dose. Cycle=28 days
Population: All participants with at least one evaluable ribociclib concentration. Number analyzed indicated the number of participants with an evaluable ribociclib concentration at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 1 Day 15 predose (ribociclib 600 mg) | 627 nanogram (ng) / miliLiter (mL) | Geometric Coefficient of Variation 67.6 |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 1 Day 15 2 hours post-dose (ribociclib 600 mg) | 1670 nanogram (ng) / miliLiter (mL) | Geometric Coefficient of Variation 52 |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 1 Day 15 4 hours post-dose (ribociclib 600 mg) | 1690 nanogram (ng) / miliLiter (mL) | Geometric Coefficient of Variation 46.2 |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 1 Day 15 6 hours post-dose (ribociclib 600 mg) | 1420 nanogram (ng) / miliLiter (mL) | Geometric Coefficient of Variation 50.9 |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 2 Day 15 predose (ribociclib 600 mg) | 553 nanogram (ng) / miliLiter (mL) | Geometric Coefficient of Variation 80.7 |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 2 Day 15 predose (ribociclib 400 mg) | 220 nanogram (ng) / miliLiter (mL) | Geometric Coefficient of Variation 81.6 |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 2 Day 15 2 hours post-dose (ribociclib 600 mg) | 1470 nanogram (ng) / miliLiter (mL) | Geometric Coefficient of Variation 80.7 |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 2 Day 15 2 hours post-dose (ribociclib 400 mg) | 794 nanogram (ng) / miliLiter (mL) | Geometric Coefficient of Variation 85 |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 2 Day 15 2 hours post-dose (ribociclib 200 mg) | 104 nanogram (ng) / miliLiter (mL) | — |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 2 Day 15 4 hours post-dose (ribociclib 600 mg) | 1610 nanogram (ng) / miliLiter (mL) | Geometric Coefficient of Variation 53.6 |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 2 Day 15 4 hours post-dose (ribociclib 400 mg) | 913 nanogram (ng) / miliLiter (mL) | Geometric Coefficient of Variation 69.4 |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 2 Day 15 4 hours post-dose (ribociclib 200 mg) | 112 nanogram (ng) / miliLiter (mL) | — |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 2 Day 15 6 hours post-dose (ribociclib 600 mg) | 1280 nanogram (ng) / miliLiter (mL) | Geometric Coefficient of Variation 89.6 |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 2 Day 15 6 hours post-dose (ribociclib 400 mg) | 710 nanogram (ng) / miliLiter (mL) | Geometric Coefficient of Variation 47.4 |
| Ribociclib + Fulvestrant | Ribociclib Plasma Concentrations | Cycle 2 Day 15 6 hours post-dose (ribociclib 200 mg) | 104 nanogram (ng) / miliLiter (mL) | — |
Secondary
Time to Definitive 10% Deterioration in the Global Health Status/Quality of Life (GHS/QoL) Scale Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)
The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, a GHS/QoL scale, and 6 single items. GHS/QoL scale scores range between 0 and 100. A high score for GHS/QoL represents better functioning or QoL. The time to definitive 10% deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10% relative to baseline worsening of the QoL score (without further improvement above the threshold) or death due to any cause. The Kaplan-Meier method was used to estimate the distribution, and the median time to definitive 10% deterioration, along with 95% confidence intervals, was reported for each treatment group. If a patient had not had an event, time to deterioration was censored at the date of the last adequate QoL evaluation.
Time frame: Up to approximately 26 months
Population: FAS including all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + Fulvestrant | Time to Definitive 10% Deterioration in the Global Health Status/Quality of Life (GHS/QoL) Scale Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30) | NA Months |
| Placebo + Fulvestrant | Time to Definitive 10% Deterioration in the Global Health Status/Quality of Life (GHS/QoL) Scale Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30) | 19.4 Months |
Secondary
Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) in One Score Category
ECOG PS categorized patients based on their ability to perform daily activities and self-care, with scores ranging from 0 to 5. A score of 0 indicated no restrictions in activity, while higher scores indicated increasing limitations. Time to definitive deterioration was defined as the time from the date of randomization to the date of the event, defined as experiencing an increase in ECOG PS by at least one category from the baseline or death. A deterioration was considered definitive if no improvements in the ECOG PS were observed at a subsequent time. The Kaplan-Meier method was used to estimate the distribution, and the median time to definitive deterioration, along with 95% confidence intervals, was reported for each treatment group. Patients receiving any further therapy prior to definitive worsening were censored at their date of last assessment prior to start of therapy. Patients that had not worsened at the data cutoff point were censored at the date of last assessment.
Time frame: Up to approximately 26 months
Population: FAS including all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + Fulvestrant | Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) in One Score Category | NA Months |
| Placebo + Fulvestrant | Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) in One Score Category | NA Months |
Secondary
Time to Response (TTR) Per Investigator Assessment
TTR was defined as the time from randomization to the first documented and confirmed response (CR or PR) as defined by RECIST 1.1 per investigator assessment. The Kaplan-Meier method was used to estimate TTR, and the median TTR, along with 95% confidence intervals, was reported for each treatment group. Participants who did not achieve a confirmed response were censored at the maximum follow-up time for patients who had a PFS event (i.e. either progressed or died due to any cause) or at the date of last adequate tumor assessment otherwise. 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: From randomization to first response, assessed up to approximately 26 months
Population: FAS including all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + Fulvestrant | Time to Response (TTR) Per Investigator Assessment | NA Months |
| Placebo + Fulvestrant | Time to Response (TTR) Per Investigator Assessment | NA Months |
Post Hoc
All Collected Deaths
Pre-treatment deaths were collected from day of participant's informed consent to the day before first dose of study medication. On-treatment deaths were collected from start of treatment to 30 days after last dose of treatment or one day before first administration of crossover treatment (for crossover participants), whichever came first Crossover on-treatment deaths were collected from start of crossover treatment up to 30 days after last dose of crossover treatment. Post-treatment efficacy/survival follow-up deaths were collected from day 31 after last dose of study treatment to end of study. Crossover post-treatment efficacy/survival follow-up deaths were collected from day 31 after last dose of crossover treatment to end of study.
Time frame: Pre-treatment: Up to 28 days prior to treatment. On-treatment: Up to 82 months. Crossover on-treatment: Up to 3.5 months. Post-treatment efficacy/survival follow-up: Up to 82 months. Crossover post-treatment efficacy/survival follow-up: Up to 1 year
Population: FAS including all randomized participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ribociclib + Fulvestrant | All Collected Deaths | On-treatment deaths | 13 Participants |
| Ribociclib + Fulvestrant | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Ribociclib + Fulvestrant | All Collected Deaths | All deaths | 277 Participants |
| Ribociclib + Fulvestrant | All Collected Deaths | Post-treatment efficacy/survival deaths | 264 Participants |
| Placebo + Fulvestrant | All Collected Deaths | Crossover post-treatment efficacy/survival deaths | 1 Participants |
| Placebo + Fulvestrant | All Collected Deaths | On-treatment deaths | 8 Participants |
| Placebo + Fulvestrant | All Collected Deaths | All deaths | 162 Participants |
| Placebo + Fulvestrant | All Collected Deaths | Pre-treatment deaths | 0 Participants |
| Placebo + Fulvestrant | All Collected Deaths | Crossover on-treatment deaths | 0 Participants |
| Placebo + Fulvestrant | All Collected Deaths | Post-treatment efficacy/survival deaths | 153 Participants |