Trial Outcomes & Findings for Study to Assess the Safety and Efficacy of Ribociclib (LEE011) in Combination With Letrozole for the Treatment of Men and Pre/Postmenopausal Women With HR+ HER2- aBC (NCT NCT02941926)

NCT ID: NCT02941926

Last Updated: 2023-10-24

Results Overview

AEs were defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s). SAEs were defined as meeting at least 1 of the following criteria: is fatal or life-threatening, Results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, requires inpatient hospitalization or prolongation of existing hospitalization. A SAE which caused death of the participant was considered as fatal SAE. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1 to 5 were used to characterize the severity of the Adverse Event. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening and Grade 5: death related to AE. A participant with multiple severity grades for an AE is only counted under the maximum grade.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

3246 participants

Primary outcome timeframe

From start of treatment up to 30 days after last treatment (for participants who did not enter to the Extension phase) or up to last treatment in the Core phase (for participants who entered the Extension phase), assessed up to approximately 33 months.

Results posted on

2023-10-24

Participant Flow

Core Phase was conducted across 514 centers in 38 countries. Extension Phase was conducted across 189 centers in 25 countries.

A total of 3694 participants were screened in this study of which 3246 participants were enrolled in the study.

Participant milestones

Participant milestones
Measure	Ribociclib + Letrozole + Goserelin/Leuprolide Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
Core Phase STARTED	3246
Core Phase Canadian Sub-study	88
Core Phase COMPLETED	1301
Core Phase NOT COMPLETED	1945
Extension Phase STARTED	413
Extension Phase COMPLETED	112
Extension Phase NOT COMPLETED	301

Reasons for withdrawal

Reasons for withdrawal
Measure	Ribociclib + Letrozole + Goserelin/Leuprolide Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
Core Phase Progressive disease	1109
Core Phase Adverse Event	504
Core Phase Subject/guardian decision	127
Core Phase Physician Decision	112
Core Phase Death	46
Core Phase Protocol deviation	34
Core Phase Lost to Follow-up	8
Core Phase Technical problems	5
Extension Phase Physician Decision	155
Extension Phase Progressive disease	115
Extension Phase Adverse Event	13
Extension Phase Subject/Guardian decision	12
Extension Phase Death	6

Baseline Characteristics

Study to Assess the Safety and Efficacy of Ribociclib (LEE011) in Combination With Letrozole for the Treatment of Men and Pre/Postmenopausal Women With HR+ HER2- aBC

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ribociclib + Letrozole + Goserelin/Leuprolide n=3246 Participants Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
Age, Continuous	58.1 Years STANDARD_DEVIATION 12.22 • n=93 Participants
Sex: Female, Male Female	3207 Participants n=93 Participants
Sex: Female, Male Male	39 Participants n=93 Participants
Race/Ethnicity, Customized Caucasian	2553 Participants n=93 Participants
Race/Ethnicity, Customized Unknown	284 Participants n=93 Participants
Race/Ethnicity, Customized Asian	227 Participants n=93 Participants
Race/Ethnicity, Customized Other	134 Participants n=93 Participants
Race/Ethnicity, Customized Black	29 Participants n=93 Participants
Race/Ethnicity, Customized Native American	18 Participants n=93 Participants
Race/Ethnicity, Customized Pacific Islander	1 Participants n=93 Participants

PRIMARY outcome

Timeframe: From start of treatment up to 30 days after last treatment (for participants who did not enter to the Extension phase) or up to last treatment in the Core phase (for participants who entered the Extension phase), assessed up to approximately 33 months.

Population: Safety set in the Core phase: All participants who received at least one dose of study treatment defined as either ribociclib, or letrozole, or goserelin, or leuprolide in the Core phase.

Outcome measures

Outcome measures
Measure	Ribociclib + Letrozole + Goserelin/Leuprolide n=3246 Participants Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.	Sensitive Cohort Participants included in the sub-study treated with ribociclib in combination with letrozole and goserelin or leuprolide (for men and premenopausal women) who were sensitive to treatment (with time to progression of 22 months or more)
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase AEs- All grades	3203 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase AEs- Grade ≥ 3	2461 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase Treatment-related AEs- All grades	3091 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase Treatment-related AEs- Grade ≥ 3	2192 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase SAEs- All grades	702 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase SAEs- Grade ≥ 3	590 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase Treatment-related SAEs- All grades	203 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase Treatment-related SAEs- Grade ≥ 3	178 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase Fatal SAEs- All grades	62 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase Treatment-related Fatal SAEs- All grades	14 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase AEs leading to discontinuation- All grades	528 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase AEs leading to discontinuation- Grade ≥ 3	310 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase Treatment-related AEs leading to discontinuation- All grades	418 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase Treatment-related AEs leading to discontinuation-Grade ≥ 3	237 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase AEs leading to dose adjustment/interruption- All grades	2434 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase AEs leading to dose adjustment/interruption- Grade ≥ 3	2095 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase Treatment-related AEs leading to dose adjustment/interruption- All grades	2235 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase Treatment-related AEs leading to dose adjustment/interruption- Grade ≥ 3	1964 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase AEs requiring additional therapy- All grades	2624 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase AEs requiring additional therapy- Grade ≥ 3	844 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase Treatment-related AEs requiring additional therapy- All grades	1613 Participants	—
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase Treatment-related AEs requiring additional therapy- Grade ≥ 3	392 Participants	—

SECONDARY outcome

Timeframe: Up to approximately 33 months

Population: Full Analysis set: All participants who received at least one dose of study treatment defined as either ribociclib, or letrozole, or goserelin, or leuprolide in the Core phase.

Time to progression (TTP) is defined as time from date of start of treatment to the date of first documented progression or death due to underlying cancer. Participants with symptoms of rapidly progressing disease without radiologic evidence were classified as progression only when clear evidence of clinical deterioration was documented and/or patient discontinued due to 'Disease progression' or death due to study indication. When there was no documentation of radiologic evidence of progression, and the patient discontinued for 'Disease progression' due to documented clinical deterioration of disease, the date of discontinuation was used as date of progression. TTP was estimated using the Kaplan-Meier method. 95% CI of median was calculated according to Brookmeyer and Crowley method.

Outcome measures

Outcome measures
Measure	Ribociclib + Letrozole + Goserelin/Leuprolide n=3246 Participants Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.	Sensitive Cohort Participants included in the sub-study treated with ribociclib in combination with letrozole and goserelin or leuprolide (for men and premenopausal women) who were sensitive to treatment (with time to progression of 22 months or more)
Time-to-Progression (TTP) Based on Investigator's Assessment (Core Phase)	27.1 Months Interval 25.7 to Upper limit was not reached (NA) due to insufficient follow up time	—

SECONDARY outcome

Timeframe: Up to approximately 33 months

Population: Full Analysis set: All participants who received at least one dose of study treatment defined as either ribociclib, or letrozole, or goserelin, or leuprolide in the Core phase.

Overall response rate (ORR) is defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 based on investigator's 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. 95% CI was calculated using the exact binomial method.

Outcome measures

Outcome measures
Measure	Ribociclib + Letrozole + Goserelin/Leuprolide n=3246 Participants Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.	Sensitive Cohort Participants included in the sub-study treated with ribociclib in combination with letrozole and goserelin or leuprolide (for men and premenopausal women) who were sensitive to treatment (with time to progression of 22 months or more)
Overall Response Rate (ORR) Based on Investigator's Assessment (Core Phase)	29.3 Percentage of participants Interval 27.7 to 30.9	—

SECONDARY outcome

Timeframe: Up to approximately 33 months

Population: Full Analysis set: All participants who received at least one dose of study treatment defined as either ribociclib, or letrozole, or goserelin, or leuprolide in the Core phase.

Clinical benefit rate (CBR) is defined as the percentage of participants with a best overall response of complete response (CR), or partial response (PR) or an overall lesion response of stable disease (SD), lasting as per local review, for a duration of at least 24 weeks. CR, PR and SD are defined according to RECIST 1.1 based on investigator's 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. 95% CI was calculated using the exact binomial method.

Outcome measures

Outcome measures
Measure	Ribociclib + Letrozole + Goserelin/Leuprolide n=3246 Participants Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.	Sensitive Cohort Participants included in the sub-study treated with ribociclib in combination with letrozole and goserelin or leuprolide (for men and premenopausal women) who were sensitive to treatment (with time to progression of 22 months or more)
Clinical Benefit Rate (CBR) Based on Investigator's Assessment (Core Phase)	70.7 Percentage of participants Interval 69.1 to 72.2	—

SECONDARY outcome

Timeframe: On Day 1 of Cycle 1, 2, 3, 4 ,5, 6, 8, 10, 12 and after that every 3 cycles, and End of treatment, assessed up to 33 months. Cycle=28 days

Population: Female participants in the Full Analysis set population for whom baseline and at least one post baseline patient-reported outcome measurements are available. Number analyzed indicates number of participants with available data for this outcome measure at specified timepoints.

Change from baseline in FACT-B scores was assessed. FACT-B is a self-report instrument that measures multidimensional quality of life (QOL) in patients with breast cancer. The FACT-B consists of 37 questions that address physical, social, emotional, and functional well-being, with specific questions relevant to women with breast cancer. Each item has a score range of 0 (Not at all) to 4 (Very much), with a total score ranging from 0-148. The higher the score, the better the QOL reported by the participant. A positive change from baseline indicates improvement in QoL. Due to the nature of the questionnaire, only females were asked to complete this questionnaire.

Outcome measures

Outcome measures
Measure	Ribociclib + Letrozole + Goserelin/Leuprolide n=1230 Participants Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.	Sensitive Cohort Participants included in the sub-study treated with ribociclib in combination with letrozole and goserelin or leuprolide (for men and premenopausal women) who were sensitive to treatment (with time to progression of 22 months or more)
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 2 Day 1	0.2 Score on a scale Standard Deviation 13.29	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 3 Day 1	0.1 Score on a scale Standard Deviation 13.72	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 4 Day 1	-0.3 Score on a scale Standard Deviation 14.90	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 5 Day 1	0.0 Score on a scale Standard Deviation 15.02	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 6 Day 1	-0.8 Score on a scale Standard Deviation 14.91	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 8 Day 1	-0.9 Score on a scale Standard Deviation 16.32	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 10 Day 1	-1.2 Score on a scale Standard Deviation 15.83	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 12 Day 1	-1.6 Score on a scale Standard Deviation 16.13	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 15 Day 1	-2.0 Score on a scale Standard Deviation 16.58	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 18 Day 1	-2.0 Score on a scale Standard Deviation 16.09	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 21 Day 1	-2.0 Score on a scale Standard Deviation 17.82	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 24 Day 1	-3.0 Score on a scale Standard Deviation 17.89	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 27 Day 1	-2.7 Score on a scale Standard Deviation 13.84	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 30 Day 1	-2.0 Score on a scale Standard Deviation 14.14	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) Cycle 33 Day 1	12.1 Score on a scale Standard Deviation 21.10	—
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) End of Treatment	-4.1 Score on a scale Standard Deviation 16.98	—

SECONDARY outcome

Timeframe: From first dose of treatment in the Extension phase up to 30 days after last dose of treatment, assessed up approximately 37.6 months

Population: Safety set in the Extension phase: all patients who received at least one dose of study medications defined as ribociclib or letrozole or goserelin/leuprolide (if applicable) in the Extension Phase.

AEs were defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s). SAEs were defined as meeting at least 1 of the following criteria: is fatal or life-threatening, Results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, requires inpatient hospitalization or prolongation of existing hospitalization. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1 to 5 were used to characterize the severity of the Adverse Event. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening and Grade 5: death related to AE. A participant with multiple severity grades for an AE is only counted under the maximum grade.

Outcome measures

Outcome measures
Measure	Ribociclib + Letrozole + Goserelin/Leuprolide n=413 Participants Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.	Sensitive Cohort Participants included in the sub-study treated with ribociclib in combination with letrozole and goserelin or leuprolide (for men and premenopausal women) who were sensitive to treatment (with time to progression of 22 months or more)
Number of Participants With AEs and SAEs in the Extension Phase AEs- All grades	297 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase AEs- Grade ≥ 3	159 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase Treatment-related AEs- All grades	221 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase Treatment-related AEs- Grade ≥ 3	123 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase SAEs- All grades	54 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase SAEs- Grade ≥ 3	45 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase Treatment-related SAEs- All grades	7 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase Treatment-related SAEs- Grade ≥ 3	6 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase Fatal SAEs- All grades	5 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase Treatment-related Fatal SAEs- All grades	0 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase AEs leading to discontinuation- All grades	17 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase AEs leading to discontinuation- Grade ≥ 3	9 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase Treatment-related AEs leading to discontinuation- All grades	7 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase Treatment-related AEs leading to discontinuation-Grade ≥ 3	4 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase AEs leading to dose adjustment/interruption- All grades	185 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase AEs leading to dose adjustment/interruption- Grade ≥ 3	132 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase Treatment-related AEs leading to dose adjustment/interruption- All grades	134 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase Treatment-related AEs leading to dose adjustment/interruption- Grade ≥ 3	113 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase AEs requiring additional therapy- All grades	186 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase AEs requiring additional therapy- Grade ≥ 3	56 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase Treatment-related AEs requiring additional therapy- All grades	47 Participants	—
Number of Participants With AEs and SAEs in the Extension Phase Treatment-related AEs requiring additional therapy- Grade ≥ 3	12 Participants	—

SECONDARY outcome

Timeframe: On Day 1 of every 3 cycles, starting from Cycle 1 of the Extension phase until end of treatment, assessed up to 37.4 months. Cycle= 28 days

Clinical benefit as assessed by the Investigator during Extension phase

Outcome measures

Outcome measures
Measure	Ribociclib + Letrozole + Goserelin/Leuprolide n=413 Participants Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.	Sensitive Cohort Participants included in the sub-study treated with ribociclib in combination with letrozole and goserelin or leuprolide (for men and premenopausal women) who were sensitive to treatment (with time to progression of 22 months or more)
Number of Participants With Clinical Benefit (Extension Phase) Cycle 1 Day 1	413 Participants	—
Number of Participants With Clinical Benefit (Extension Phase) Cycle 4 Day 1	386 Participants	—
Number of Participants With Clinical Benefit (Extension Phase) Cycle 7 Day 1	353 Participants	—
Number of Participants With Clinical Benefit (Extension Phase) Cycle 10 Day 1	323 Participants	—
Number of Participants With Clinical Benefit (Extension Phase) Cycle 13 Day 1	245 Participants	—
Number of Participants With Clinical Benefit (Extension Phase) Cycle 16 Day 1	200 Participants	—
Number of Participants With Clinical Benefit (Extension Phase) Cycle 19 Day 1	183 Participants	—
Number of Participants With Clinical Benefit (Extension Phase) Cycle 22 Day 1	118 Participants	—
Number of Participants With Clinical Benefit (Extension Phase) Cycle 25 Day 1	55 Participants	—
Number of Participants With Clinical Benefit (Extension Phase) Cycle 28 Day 1	51 Participants	—
Number of Participants With Clinical Benefit (Extension Phase) Cycle 31 Day 1	44 Participants	—
Number of Participants With Clinical Benefit (Extension Phase) Cycle 34 Day 1	32 Participants	—
Number of Participants With Clinical Benefit (Extension Phase) Cycle 37 Day 1	24 Participants	—
Number of Participants With Clinical Benefit (Extension Phase) Cycle 40 Day 1	5 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Screening (up to 28 days before first dose of study treatment)

Population: Participants included in the sub-study (only available for Canadian participants) with evaluable tumor samples collected during screening in the main study and with time to progression within 3 months (cohort not achieving clinical benefit) or with time to progression of 22 months or more (cohort sensitive to treatment)

Exploratory analysis performed in archival tumor samples collected during screening in the main study. Protein expression levels of the ribociclib plus letrozole cohort that did not achieve clinical benefit (progression within 3 months of treatment) and the cohort sensitive to ribociclib and letrozole (cohort with a time to progression of 22 months or more) were determined using using Single-Pot, Solid-Phase-enhanced, Sample Preparation-Clinical Tissue Proteomics (SP3-CTP). For normalization purposes a pooled internal standard sample, comprised of aliquots of every sample included in the study, was included in each experimental batch. Protein abundances were calculated as the log2 transformed abundances relative to the pooled internal standard. Positive values represent higher protein expression levels compared to the pooled internal standard. Expression levels of proteins that showed association to predicting response to study treatment are presented.

Outcome measures

POST_HOC outcome

Timeframe: On-treatment Core Phase: up to 33 months; Post-treatment survival Follow-up Core Phase: Up to 33 months; On-treatment Extension Phase: up to approximately 37.6 months; Post-treatment survival Follow-up Extension Phase: Up to approximately 37.6 months.

Population: Core phase: All participants who received at least one dose of study treatment defined as either ribociclib, or letrozole, or goserelin, or leuprolide in the Core phase. Extension phase: all patients who received at least one dose of study medications defined as ribociclib or letrozole or goserelin/leuprolide (if applicable) in the Extension phase.

On-treatment- Core phase: from first treatment in the Core phase up to 30 days post-treatment (for participants who did not enter the Extension phase) or up to last treatment in the Core phase (for participants who entered the Extension phase). Extension phase: from first dose of treatment in the Extension phase up to 30 days after last dose of treatment. Post-treatment survival follow-up- Core phase: from 31 days post-treatment in the core phase up to end of study; Extension phase: from 31 days post-treatment in the Extension phase up to end of study.

Outcome measures

Outcome measures
Measure	Ribociclib + Letrozole + Goserelin/Leuprolide n=3246 Participants Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.	Sensitive Cohort Participants included in the sub-study treated with ribociclib in combination with letrozole and goserelin or leuprolide (for men and premenopausal women) who were sensitive to treatment (with time to progression of 22 months or more)
All Collected Deaths On-treatment Core Phase	74 Participants	—
All Collected Deaths Post-treatment survival follow-up Core Phase	90 Participants	—
All Collected Deaths All deaths Core Phase	164 Participants	—
All Collected Deaths On-treatment Extension Phase	5 Participants	—
All Collected Deaths Post-treatment survival follow-up Extension Phase	3 Participants	—
All Collected Deaths All deaths Extension Phase	8 Participants	—

Adverse Events

All Patients- On-treatment Core Phase

Serious events: 702 serious events

Other events: 3150 other events

Deaths: 74 deaths

All Patients- On-treatment Extension Phase

Serious events: 54 serious events

Other events: 247 other events

Deaths: 5 deaths

All-patients- Post-treatment Survival Follow-up Core Phase

Serious events: 0 serious events

Other events: 0 other events

Deaths: 90 deaths

All-patients- Post-treatment Survival Follow-up Extension Phase

Serious events: 0 serious events

Other events: 0 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Study director

Novartis Pharmaceuticals

Phone: + 1 862 778 8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Ribociclib + Letrozole + Goserelin/Leuprolide n=8 Participants Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.	Sensitive Cohort n=19 Participants Participants included in the sub-study treated with ribociclib in combination with letrozole and goserelin or leuprolide (for men and premenopausal women) who were sensitive to treatment (with time to progression of 22 months or more)
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Isocitrate dehydrogenase [NADP] cytoplasmic (IDH1)	0.112 log2 transformed relative ratio Standard Deviation 0.500	-0.218 log2 transformed relative ratio Standard Deviation 0.352
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Retinal dehydrogenase 1 (ALDH1A1)	0.022 log2 transformed relative ratio Standard Deviation 0.446	-0.325 log2 transformed relative ratio Standard Deviation 0.147
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Coagulation factor XIII A chain (F13A1)	-0.378 log2 transformed relative ratio Standard Deviation 0.263	-0.010 log2 transformed relative ratio Standard Deviation 0.198
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Argininosuccinate synthase (ASS1)	0.104 log2 transformed relative ratio Standard Deviation 0.612	-0.466 log2 transformed relative ratio Standard Deviation 0.129
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Heat shock protein beta-1 (HSPB1)	-0.546 log2 transformed relative ratio Standard Deviation 0.113	-0.151 log2 transformed relative ratio Standard Deviation 0.270
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Aldehyde dehydrogenase, mitochondrial (ALDH2)	0.319 log2 transformed relative ratio Standard Deviation 0.571	-0.077 log2 transformed relative ratio Standard Deviation 0.374
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Decorin (DCN)	-0.456 log2 transformed relative ratio Standard Deviation 0.266	-0.033 log2 transformed relative ratio Standard Deviation 0.568
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Cathepsin G (CTSG)	-0.634 log2 transformed relative ratio Standard Deviation 0.191	-0.175 log2 transformed relative ratio Standard Deviation 0.274
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Pyruvate carboxylase, mitochondrial (PC)	0.413 log2 transformed relative ratio Standard Deviation 0.649	-0.004 log2 transformed relative ratio Standard Deviation 0.181
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1)	0.033 log2 transformed relative ratio Standard Deviation 0.254	-0.129 log2 transformed relative ratio Standard Deviation 0.087
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Collagen alpha-3(VI) chain (COL6A3)	-0.186 log2 transformed relative ratio Standard Deviation 0.187	-0.015 log2 transformed relative ratio Standard Deviation 0.186
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Versican core protein (VCAN)	-0.301 log2 transformed relative ratio Standard Deviation 0.242	0.141 log2 transformed relative ratio Standard Deviation 0.581
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Fibulin-1 (FBLN1)	-0.245 log2 transformed relative ratio Standard Deviation 0.313	0.128 log2 transformed relative ratio Standard Deviation 0.435
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Acetyl-CoA acetyltransferase, mitochondrial (ACAT1)	0.135 log2 transformed relative ratio Standard Deviation 0.409	-0.074 log2 transformed relative ratio Standard Deviation 0.136
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Long-chain-fatty-acid--CoA ligase 1 (ACSL1)	0.296 log2 transformed relative ratio Standard Deviation 1.056	-0.144 log2 transformed relative ratio Standard Deviation 0.205
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Pigment epithelium-derived factor (SERPINF1)	-0.378 log2 transformed relative ratio Standard Deviation 0.161	0.169 log2 transformed relative ratio Standard Deviation 0.662
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2)	0.258 log2 transformed relative ratio Standard Deviation 0.501	-0.080 log2 transformed relative ratio Standard Deviation 0.166
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Fatty acid synthase (FASN)	-0.198 log2 transformed relative ratio Standard Deviation 0.198	0.038 log2 transformed relative ratio Standard Deviation 0.284
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Lumican (LUM)	-0.355 log2 transformed relative ratio Standard Deviation 0.182	0.010 log2 transformed relative ratio Standard Deviation 0.399
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Fibulin-2 (FBLN2)	-0.208 log2 transformed relative ratio Standard Deviation 0.098	0.075 log2 transformed relative ratio Standard Deviation 0.271
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Prolow-density lipoprotein receptor-related protein 1 (LRP1)	-0.148 log2 transformed relative ratio Standard Deviation 0.118	0.094 log2 transformed relative ratio Standard Deviation 0.194
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Galectin-3-binding protein (LGALS3BP)	-0.491 log2 transformed relative ratio Standard Deviation 0.134	-0.126 log2 transformed relative ratio Standard Deviation 0.213
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Inactive tyrosine-protein kinase 7 (PTK7)	-0.251 log2 transformed relative ratio Standard Deviation 0.071	0.070 log2 transformed relative ratio Standard Deviation 0.237
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Ras GTPase-activating-like protein IQGAP2 (IQGAP2)	0.318 log2 transformed relative ratio Standard Deviation 0.538	-0.036 log2 transformed relative ratio Standard Deviation 0.221
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Spectrin alpha chain, non-erythrocytic 1 (SPTAN1)	0.085 log2 transformed relative ratio Standard Deviation 0.323	-0.082 log2 transformed relative ratio Standard Deviation 0.123
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Periostin (POSTN)	-0.419 log2 transformed relative ratio Standard Deviation 0.165	0.051 log2 transformed relative ratio Standard Deviation 0.393
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Procollagen C-endopeptidase enhancer 1 (PCOLCE)	-0.217 log2 transformed relative ratio Standard Deviation 0.172	0.184 log2 transformed relative ratio Standard Deviation 0.375
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole CD109 antigen (CD109)	-0.213 log2 transformed relative ratio Standard Deviation 0.141	0.043 log2 transformed relative ratio Standard Deviation 0.145
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Palladin (PALLD)	-0.207 log2 transformed relative ratio Standard Deviation 0.137	0.050 log2 transformed relative ratio Standard Deviation 0.221
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Collagen triple helix repeat-containing protein 1 (CTHRC1)	-0.514 log2 transformed relative ratio Standard Deviation 0.156	0.176 log2 transformed relative ratio Standard Deviation 0.387
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Collagen alpha-1(XII) chain (COL12A1)	-0.302 log2 transformed relative ratio Standard Deviation 0.183	0.230 log2 transformed relative ratio Standard Deviation 1.041
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole Matrix-remodeling-associated protein 5 (MXRA5)	-0.221 log2 transformed relative ratio Standard Deviation 0.192	0.205 log2 transformed relative ratio Standard Deviation 0.431
Canadian Sub-study: Proteomic Analysis of Ribociclib and Letrozole Cohort Not Achieving Clinical Benefit Compared to a Cohort Sensitive to Treatment With Ribociclib and Letrozole C-type mannose receptor 2 (MRC2)	-0.201 log2 transformed relative ratio Standard Deviation 0.124	0.170 log2 transformed relative ratio Standard Deviation 0.274