Advanced Metastatic Breast Cancer
Conditions
Keywords
LEE011, ribociclib, HR-positive, HER2-negative, Advanced breast cancer, Letrozole, Anastrozole, Tamoxifen, Goserelin, CDK, CDK4, CDK6, CDK4/6, Phase III, ER-positive, PR-positive, Premenopausal
Brief summary
The purpose of this study was to determine whether treatment with tamoxifen or a non-steroidal aromatase inhibitors (NSAI) + goserelin + LEE011 prolonged progression-free survival (PFS) compared to treatment with tamoxifen or a NSAI + goserelin + placebo in premenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer.
Detailed description
This was a randomized, Phase III, double-blind, global study comparing the treatment efficacy and safety of ribociclib + goserelin + tamoxifen or a NSAI (letrozole or anastrozole) versus placebo + goserelin + tamoxifen or a NSAI in premenopausal women with HR+, HER2- advanced breast cancer. Eligible participants were randomized in a 1:1 ratio to either the ribociclib arm or the placebo arm. Study treatment continued until disease progression, unacceptable toxicity, death, or discontinuation for any other reason. 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 (post-treatment efficacy follow-up). All participants who discontinued treatment were followed for survival until the predetermined number of overall survival (OS) events was reached. Following the final OS analysis (performed when approximately 189 deaths were recorded) and with protocol amendment 6 (dated 18-Jul-2019), participants and investigators were unblinded and those participants in the placebo arm had the opportunity to cross-over to the ribociclib arm to receive ribociclib + goserelin + NSAI. Cross-over was optional and was conducted at the investigator's discretion and upon participant consent.
Interventions
DRUGRibociclib
Ribociclib (600 mg, in three 200 mg hard gelatin capsules) was administered orally once daily on Days 1-21 of each 28-day cycle.
DRUGTamoxifen
Tamoxifen (20 mg, tablets) was administered orally on a continuous daily schedule (days 1-28 of each 28-day cycle)
DRUGLetrozole
Letrozole (2.5 mg, tablets) was administered orally once daily on a continuous daily schedule (days 1-28 of each 28-day cycle)
DRUGAnastrozole
Anastrozole (1 mg, tablets) was administered orally once daily on a continuous daily schedule (days 1-28 of each 28-day cycle)
DRUGGoserelin
Goserelin (3.6 mg, subcutaneous implant) was administered on day 1 of every 28-day cycle
DRUGPlacebo
Placebo (hard gelatin capsules) was administered orally once daily on Days 1-21 of each 28-day cycle.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 59 Years
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria: * Patients had advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy * Patients were premenopausal or perimenopausal at the time of study entry * Patients who had received (neo) adjuvant therapy for breast cancer were eligible * Patients had a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer * Patients had HER2-negative breast cancer * Patients must have either had measurable disease or If no measurable disease was present, then at least one predominantly lytic bone lesion * Patients had an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Patients had adequate bone marrow and organ function Key
Exclusion criteria
* Patients who had received a prior CDK4/6 inhibitor * Patients were postmenopausal * Patients who currently had inflammatory breast cancer at screening. * Patients who had received any prior hormonal anti-cancer therapy for advanced breast cancer, except for ≤ 14 days of tamoxifen or NSAI ± goserelin for advanced breast cancer prior to randomization. * Patients had a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated basal cell skin carcinoma, squamous cell skin carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer. * Patients with CNS metastases. * Patients had active cardiac disease or a history of cardiac dysfunction * Patients were currently using other antineoplastic agents * Patients were pregnant or nursing or physiologically capable of becoming pregnant and not using highly effective contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) by Investigator Assessment | From randomization to first documented progression or death, assessed up to approximately 29 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. As per protocol, the final PFS analysis was conducted after approximately 392 PFS events were documented. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group. A stratified Cox regression model was used to estimate the hazard ratio of PFS, along with 95% confidence interval |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) by Investigator Assessment | Up to approximately 29 months | ORR is the percentage of participants with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 as per local assessment. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 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) by Investigator Assessment | Up to approximately 29 months | Percentage of participants with complete response (CR) or partial response (PR) or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1 and local assessment. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 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: PD = At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20% the sum must also demonstrate an absolute increase of at least 5 mm. |
| Time to Response (TTR) by Investigator Assessment | Up to approximately 29 months | Time to response is the time from the date of randomization to the first documented response (CR or PR, which must be confirmed subsequently) according to RECIST 1.1 as per local 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 non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 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 45 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. OS was estimated using the Kaplan-Meier method. As per protocol, the final OS analysis was conducted after approximately 189 deaths were documented. The median OS, along with 95% confidence intervals, 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 Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score | Baseline, up to approximately 29 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. |
| 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 29 months | The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges 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 2 cycles after randomization during 18 months, then every 3 cycles up to end of treatment (EOT); EOT; and every 8 or 12 weeks post-treatment until progression, assessed up to approximately 29 months. Cycle=28 days | The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges 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 indicated 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. |
| Duration of Response (DOR) by Investigator Assessment | Up to approximately 29 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 non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 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, Australia, Belgium, Brazil, Bulgaria, Canada, Colombia, France, Germany, Greece, Hong Kong, Hungary, India, Italy, Lebanon, Malaysia, Mexico, Poland, Portugal, Russia, Saudi Arabia, Singapore, South Korea, Spain, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Arab Emirates, United States
Participant flow
Recruitment details
Participants were enrolled in 185 sites across 30 countries.
Pre-assignment details
Screening assessments were conducted up to 28 days prior to the randomization
Participants by arm
| Arm | Count |
|---|---|
| Ribociclib + NSAI/Tamoxifen + Goserelin Ribociclib 600 mg daily oral (3 weeks on/ 1 week off) in combination with NSAI or tamoxifen (tamoxifen 20 mg daily oral or letrozole 2.5 mg daily oral or anastrozole 1 mg daily oral) and goserelin 3.6 mg subcutaneous injection (once every 28 days) | 335 |
| Placebo + NSAI/Tamoxifen+ Goserelin Placebo daily oral (3 weeks on/ 1 week off) in combination with NSAI or tamoxifen (tamoxifen 20 mg daily oral or letrozole 2.5 mg daily oral or anastrozole 1 mg daily oral) and goserelin 3.6 mg subcutaneous injection (once every 28 days).
Participants were unblinded once the final OS analysis was conducted and after the implementation of protocol amendment 6 (16-Jul-2019) and were given the option to crossover to treatment with ribociclib +NSAI/tamoxifen + goserelin | 337 |
| Total | 672 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Post-treatment Efficacy Follow-up | Death | 0 | 1 |
| Post-treatment Efficacy Follow-up | Physician Decision | 1 | 1 |
| Post-treatment Efficacy Follow-up | Progressive disease | 12 | 7 |
| Post-treatment Efficacy Follow-up | Study terminated as per protocol | 8 | 3 |
| Post-treatment Efficacy Follow-up | Subject/guardian decision | 1 | 2 |
| Treatment Period | Adverse Event | 16 | 14 |
| Treatment Period | Death | 3 | 3 |
| Treatment Period | Lost to Follow-up | 2 | 0 |
| Treatment Period | Physician Decision | 14 | 27 |
| Treatment Period | Progressive disease | 234 | 260 |
| Treatment Period | Protocol deviation | 0 | 2 |
| Treatment Period | Study terminated as per protocol | 43 | 11 |
| Treatment Period | Subject/guardian decision | 23 | 20 |
Baseline characteristics
| Characteristic | Ribociclib + NSAI/Tamoxifen + Goserelin | Placebo + NSAI/Tamoxifen+ Goserelin | Total |
|---|---|---|---|
| Age, Continuous | 42.6 Years STANDARD_DEVIATION 6.6 | 43.7 Years STANDARD_DEVIATION 6.17 | 43.1 Years STANDARD_DEVIATION 6.4 |
| Race/Ethnicity, Customized Asian | 99 Participants | 99 Participants | 198 Participants |
| Race/Ethnicity, Customized Black | 10 Participants | 9 Participants | 19 Participants |
| Race/Ethnicity, Customized Caucasian | 187 Participants | 201 Participants | 388 Participants |
| Race/Ethnicity, Customized Native American | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Other | 16 Participants | 7 Participants | 23 Participants |
| Race/Ethnicity, Customized Unknown | 20 Participants | 18 Participants | 38 Participants |
| Sex: Female, Male Female | 335 Participants | 337 Participants | 672 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 | 5 / 335 | 6 / 337 | 0 / 17 | 168 / 251 | 202 / 293 | 1 / 17 |
| other Total, other adverse events | 326 / 335 | 312 / 337 | 14 / 17 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 81 / 335 | 49 / 337 | 1 / 17 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Progression Free Survival (PFS) by 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. As per protocol, the final PFS analysis was conducted after approximately 392 PFS events were documented. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group. A stratified Cox regression model was used to estimate the hazard ratio of PFS, along with 95% confidence interval
Time frame: From randomization to first documented progression or death, assessed up to approximately 29 months
Population: The Full Analysis Set (FAS) including all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + NSAI/Tamoxifen + Goserelin | Progression Free Survival (PFS) by Investigator Assessment | 23.8 Months |
| Placebo + NSAI/Tamoxifen+ Goserelin | Progression Free Survival (PFS) by Investigator Assessment | 13.0 Months |
p-value: <1e-795% CI: [0.441, 0.694]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, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges 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 indicated 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 2 cycles after randomization during 18 months, then every 3 cycles up to end of treatment (EOT); EOT; and every 8 or 12 weeks post-treatment until progression, assessed up to approximately 29 months. Cycle=28 days
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 + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post-end of treatment 5 | 16.7 Score on a Scale | — |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 5 Day 1 | 5.1 Score on a Scale | Standard Deviation 21.81 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 7 Day 1 | 5.0 Score on a Scale | Standard Deviation 21.67 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 9 Day 1 | 4.8 Score on a Scale | Standard Deviation 22.37 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 11 Day 1 | 4.3 Score on a Scale | Standard Deviation 22.17 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 13 Day 1 | 4.7 Score on a Scale | Standard Deviation 21.14 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 15 Day 1 | 4.8 Score on a Scale | Standard Deviation 22.44 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 17 Day 1 | 4.0 Score on a Scale | Standard Deviation 20.6 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 19 Day 1 | 5.5 Score on a Scale | Standard Deviation 22.12 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 22 Day 1 | 7.6 Score on a Scale | Standard Deviation 25.43 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 25 Day 1 | 5.2 Score on a Scale | Standard Deviation 19.41 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 28 Day 1 | 7.9 Score on a Scale | Standard Deviation 19.54 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 31 Day 1 | 8.3 Score on a Scale | Standard Deviation 11.79 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | End of treatment | -4.4 Score on a Scale | Standard Deviation 27.78 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post-end of treatment 1 | 3.7 Score on a Scale | Standard Deviation 25.38 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post-end of treatment 2 | 5.6 Score on a Scale | Standard Deviation 12.73 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post-end of treatment 3 | 8.3 Score on a Scale | Standard Deviation 14.43 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post-end of treatment 4 | 11.1 Score on a Scale | Standard Deviation 17.35 |
| Ribociclib + NSAI/Tamoxifen + Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 3 Day 1 | 4.6 Score on a Scale | Standard Deviation 21.64 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 3 Day 1 | 5.0 Score on a Scale | Standard Deviation 22.1 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 22 Day 1 | -3.4 Score on a Scale | Standard Deviation 25.43 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 5 Day 1 | 5.1 Score on a Scale | Standard Deviation 20.6 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post-end of treatment 4 | -8.3 Score on a Scale | — |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 7 Day 1 | 4.0 Score on a Scale | Standard Deviation 22.57 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 25 Day 1 | -0.3 Score on a Scale | Standard Deviation 25.51 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 9 Day 1 | 3.7 Score on a Scale | Standard Deviation 23.76 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post-end of treatment 1 | 6.8 Score on a Scale | Standard Deviation 32.02 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 11 Day 1 | 4.4 Score on a Scale | Standard Deviation 24.53 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 28 Day 1 | -8.3 Score on a Scale | Standard Deviation 30.28 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 13 Day 1 | 3.9 Score on a Scale | Standard Deviation 25.19 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post-end of treatment 3 | -4.2 Score on a Scale | Standard Deviation 5.89 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 15 Day 1 | 3.2 Score on a Scale | Standard Deviation 24.91 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 31 Day 1 | -8.3 Score on a Scale | — |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 17 Day 1 | 2.7 Score on a Scale | Standard Deviation 25.68 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Post-end of treatment 2 | 0.0 Score on a Scale | Standard Deviation 11.79 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | Cycle 19 Day 1 | -1.2 Score on a Scale | Standard Deviation 24.1 |
| Placebo + NSAI/Tamoxifen+ Goserelin | Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 | End of treatment | -3.0 Score on a Scale | Standard Deviation 23.41 |
Secondary
Clinical Benefit Rate (CBR) by Investigator Assessment
Percentage of participants with complete response (CR) or partial response (PR) or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1 and local assessment. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 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: PD = At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20% the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Up to approximately 29 months
Population: FAS including all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribociclib + NSAI/Tamoxifen + Goserelin | Clinical Benefit Rate (CBR) by Investigator Assessment | 79.1 Percentage of participants |
| Placebo + NSAI/Tamoxifen+ Goserelin | Clinical Benefit Rate (CBR) by Investigator Assessment | 69.7 Percentage of participants |
p-value: 0.002Cochran-Mantel-Haenszel
Secondary
Duration of Response (DOR) by 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 non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 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 29 months
Population: Randomized participants with confirmed CR or PR as per investigator assessment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + NSAI/Tamoxifen + Goserelin | Duration of Response (DOR) by Investigator Assessment | 21.3 Months |
| Placebo + NSAI/Tamoxifen+ Goserelin | Duration of Response (DOR) by Investigator Assessment | 17.5 Months |
Secondary
Overall Response Rate (ORR) by Investigator Assessment
ORR is the percentage of participants with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 as per local assessment. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 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 29 months
Population: FAS including all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribociclib + NSAI/Tamoxifen + Goserelin | Overall Response Rate (ORR) by Investigator Assessment | 40.9 Percentage of participants |
| Placebo + NSAI/Tamoxifen+ Goserelin | Overall Response Rate (ORR) by Investigator Assessment | 29.7 Percentage of participants |
p-value: 0.00098Cochran-Mantel-Haenszel
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. OS was estimated using the Kaplan-Meier method. As per protocol, the final OS analysis was conducted after approximately 189 deaths were documented. The median OS, along with 95% confidence intervals, 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 45 months
Population: FAS including all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + NSAI/Tamoxifen + Goserelin | Overall Survival (OS) | NA Months |
| Placebo + NSAI/Tamoxifen+ Goserelin | Overall Survival (OS) | 40.9 Months |
p-value: 0.0097395% CI: [0.535, 0.948]Log Rank
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, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges 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 29 months
Population: FAS including all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + NSAI/Tamoxifen + Goserelin | 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 + NSAI/Tamoxifen+ Goserelin | 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) | 21.2 Months |
Secondary
Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score
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: Baseline, up to approximately 29 months
Population: FAS including all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + NSAI/Tamoxifen + Goserelin | Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score | NA Months |
| Placebo + NSAI/Tamoxifen+ Goserelin | Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score | NA Months |
Secondary
Time to Response (TTR) by Investigator Assessment
Time to response is the time from the date of randomization to the first documented response (CR or PR, which must be confirmed subsequently) according to RECIST 1.1 as per local 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 non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 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 29 months
Population: FAS including all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + NSAI/Tamoxifen + Goserelin | Time to Response (TTR) by Investigator Assessment | NA months |
| Placebo + NSAI/Tamoxifen+ Goserelin | Time to Response (TTR) by Investigator Assessment | NA months |
Post Hoc
All Collected Deaths
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 survival follow-up deaths were collected from day 31 after last dose of study treatment to end of study or one day before first administration of crossover treatment Crossover post-treatment survival follow-up deaths were collected from day 31 after last dose of crossover treatment to end of study
Time frame: On-treatment: Up to 90 months. Crossover on-treatment: Up to approximately 33 months after crossing-over. Post-treatment survival follow-up: Up to 90 months. Crossover post-treatment survival follow-up: Up to approximately 33 months after crossing-over
Population: FAS including all randomized participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ribociclib + NSAI/Tamoxifen + Goserelin | All Collected Deaths | Post-treatment survival follow-up deaths | 168 Participants |
| Ribociclib + NSAI/Tamoxifen + Goserelin | All Collected Deaths | All deaths | 173 Participants |
| Ribociclib + NSAI/Tamoxifen + Goserelin | All Collected Deaths | On-treatment deaths | 5 Participants |
| Placebo + NSAI/Tamoxifen+ Goserelin | All Collected Deaths | Post-treatment survival follow-up deaths | 202 Participants |
| Placebo + NSAI/Tamoxifen+ Goserelin | All Collected Deaths | Crossover post-treatment survival deaths | 1 Participants |
| Placebo + NSAI/Tamoxifen+ Goserelin | All Collected Deaths | All deaths | 209 Participants |
| Placebo + NSAI/Tamoxifen+ Goserelin | All Collected Deaths | On-treatment deaths | 6 Participants |
| Placebo + NSAI/Tamoxifen+ Goserelin | All Collected Deaths | Crossover on-treatment deaths | 0 Participants |