Breast Cancer
Conditions
Keywords
HR-positive HER2-negative, advanced breast cancer, LEE011, ribociclib, letrozole, goserelin, CDK, CDK4, CDK6, CDK4/6, Phase IIIb, ER-positive, PR-positive, premenopausal, postmenopausal, men with advanced breast cancer
Brief summary
The purpose of this study is to collect additional safety and efficacy data for the combination of ribociclib + letrozole in men and pre/postmenopausal women with HR+HER2- advanced breast cancer and no prior hormonal treatment for advanced disease..
Detailed description
This was an open-label, single arm, multi-center Phase IIIb study. The study was composed of 2 phases: Core Phase and Extension Phase. In the Core Phase, safety and efficacy data was collected. The study treatment during the Core Phase was provided until disease progression, death, unacceptable toxicities, physician's decision, subject/guardian's decision, protocol deviation, study termination by sponsor, lost to follow-up, technical problems or up to 18 months after LPFV. In the event that patients were still deriving benefit at the end of the Core phase and ribociclib was not approved or available and reimbursed, patients were transitioned to the Extension Phase and continued to receive study treatment until progression, intolerance, death or physician/patient decision. Only safety and clinical benefit (as assessed by investigator) data was collected in the Extension Phase. During the Extension Phase, if ribociclib became locally approved and reimbursed, patients were to be transitioned to prescription. Patients who completed the Extension Phase and continued to derive clinical benefit from the treatment based on the investigator's evaluation received ribociclib from prescription (if approved and reimbursed), another post-trial access program, or other drug access/support program(s). Canadian sub-study: this sub-study was a multicenter Canadian exploratory correlative sample collection sub-study that aimed to better understand mechanisms of response and resistance to ribociclib in combination with letrozole therapy. This sub-study was available for all Canadian subjects enrolled on the main study and did not alter the planned treatment.
Interventions
DRUGRibociclib
Ribociclib was centrally supplied to the investigators and administered orally once a day on days 1-21 of each 28 day cycle at a starting dose of 600 mg daily
DRUGLetrozole
Letrozole was procured locally and administered orally once a day on a continuous daily schedule at a dose of 2.5 mg
DRUGGoserelin
Goserelin was procured locally and administered in men and premenopausal women as an injectable subcutaneous implant administered on day 1 starting at Cycle 1 and then every 28 days at a dose of 3.6 mg (cycle = 28 days)
DRUGLeuprolide
Leuprolide was procured locally and administered in men and premenopausal women as an injectable intramuscular depot administered on day 1 starting at Cycle 1 and then every 28 days at a dose of 7.5 mg (cycle= 28 days)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Male or female advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy. * In the case of women, both pre/perimenopausal and postmenopausal patients were allowed to be included in this study; menopausal status was relevant for the requirement of goserelin to be used concomitantly with ribociclib and letrozole. 1. Postmenopausal status was defined either by: I).Prior bilateral oophorectomy OR ii). Age ≥ 60 OR iii). Age \< 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range. If patient was taking tamoxifen or toremifene and age \< 60, then FSH and plasma estradiol levels would be in post-menopausal range per local normal range (NCCN Guidelines version 2.2017). Note: For women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol were needed to ensure menopausal status. 2. Premenopausal status was defined as either: I).Patient had last menstrual period within the last 12 months OR ii). If on tamoxifen or toremifene within the past 14 days, plasma estradiol and FSH must be in the premenopausal range per local normal range OR iii). In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range. 3. Perimenopausal status was define as neither premenopausal nor postmenopausal * Patient had a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory. * Patient had HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test was required by local laboratory testing. * Patient had an Eastern Cooperative Oncology Group (ECOG) performance status ≤2 * Patient had adequate bone marrow and organ function as defined by ALL of the following laboratory values (as assessed by local laboratory): * Absolute neutrophil count ≥ 1.5 × 10\^9/L * Platelets ≥ 100 × 10\^9/L * Hemoglobin ≥ 9.0 g/dL * Potassium, sodium, calcium corrected for serum albumin and magnesium within normal limits or corrected to within normal limits with supplements before first dose of the study medication * INR ≤1.5 * Serum creatinine \<1.5 mg/dl or creatinine clearance≥50 mL/min * In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be below 2.5 × ULN. If the patient had liver metastases, ALT and AST should be \< 5 × ULN. * Total serum bilirubin \< ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with well-documented Gilbert's Syndrome * Patient must have had a 12-lead ECG with ALL of the following parameters at screening: * QTcF interval at screening \<450 msec (using Fridericia's correction) * Resting heart rate ≥ 50 bpm Key
Exclusion criteria
* Patient who received any CDK4/6 inhibitor * Patient who received any prior systemic hormonal therapy for advanced breast cancer; no more than one prior regimen of chemotherapy for the treatment of metastatic disease was permitted. Note: * Patients who received (neo) adjuvant therapy for breast cancer were eligible. If the prior neo (adjuvant) therapy included letrozole or anastrozole the disease free interval had to be greater than 12 months from the completion of treatment until study entry. * Patients who received ≤ 28 days of letrozole or anastrozole for advanced disease prior to inclusion in this trial were eligible. * Any prior (neo) adjuvant anti-cancer therapy or prior chemotherapy for metastatic disease had to be stopped at least 5 half-lives or 7 days, whichever was longer, before study inclusion. * Patient was concurrently using other anti-cancer therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core Phase | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-to-Progression (TTP) Based on Investigator's Assessment (Core Phase) | Up to approximately 33 months | 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. |
| Overall Response Rate (ORR) Based on Investigator's Assessment (Core Phase) | Up to approximately 33 months | 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. |
| Clinical Benefit Rate (CBR) Based on Investigator's Assessment (Core Phase) | Up to approximately 33 months | 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. |
| Number of Participants With AEs and SAEs in the Extension Phase | From first dose of treatment in the Extension phase up to 30 days after last dose of treatment, assessed up approximately 37.6 months | 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. |
| Number of Participants With Clinical Benefit (Extension Phase) | 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 |
| Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase) | 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 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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 | Screening (up to 28 days before first dose of study 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. |
Countries
Argentina, Austria, Belgium, Bulgaria, Canada, Chile, Czechia, Denmark, Finland, France, Greece, Hong Kong, Hungary, India, Israel, Italy, Jordan, Lebanon, Malaysia, Mexico, Netherlands, Norway, Oman, Panama, Philippines, Poland, Portugal, Russia, Saudi Arabia, Singapore, Slovakia, Slovenia, Spain, Sweden, Taiwan, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Core Phase was conducted across 514 centers in 38 countries. Extension Phase was conducted across 189 centers in 25 countries.
Pre-assignment details
A total of 3694 participants were screened in this study of which 3246 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 3,246 |
| Total | 3,246 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Core Phase | Adverse Event | 504 |
| Core Phase | Death | 46 |
| Core Phase | Lost to Follow-up | 8 |
| Core Phase | Physician Decision | 112 |
| Core Phase | Progressive disease | 1,109 |
| Core Phase | Protocol deviation | 34 |
| Core Phase | Subject/guardian decision | 127 |
| Core Phase | Technical problems | 5 |
| Extension Phase | Adverse Event | 13 |
| Extension Phase | Death | 6 |
| Extension Phase | Physician Decision | 155 |
| Extension Phase | Progressive disease | 115 |
| Extension Phase | Subject/Guardian decision | 12 |
Baseline characteristics
| Characteristic | Ribociclib + Letrozole + Goserelin/Leuprolide |
|---|---|
| Age, Continuous | 58.1 Years STANDARD_DEVIATION 12.22 |
| Race/Ethnicity, Customized Asian | 227 Participants |
| Race/Ethnicity, Customized Black | 29 Participants |
| Race/Ethnicity, Customized Caucasian | 2553 Participants |
| Race/Ethnicity, Customized Native American | 18 Participants |
| Race/Ethnicity, Customized Other | 134 Participants |
| Race/Ethnicity, Customized Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized Unknown | 284 Participants |
| Sex: Female, Male Female | 3207 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 74 / 3,246 | 5 / 413 | 90 / 2,759 | 3 / 408 |
| other Total, other adverse events | 3,150 / 3,246 | 247 / 413 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 702 / 3,246 | 54 / 413 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Treatment With Ribociclib + Letrozole in the Core 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. 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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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
Change From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Score (Core Phase)
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 14.9 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 21.1 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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
Clinical Benefit Rate (CBR) Based on Investigator's Assessment (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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribociclib + Letrozole + Goserelin/Leuprolide | Clinical Benefit Rate (CBR) Based on Investigator's Assessment (Core Phase) | 70.7 Percentage of participants |
Secondary
Number of Participants With AEs and SAEs 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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | AEs leading to discontinuation- Grade ≥ 3 | 9 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | Treatment-related AEs leading to dose adjustment/interruption- Grade ≥ 3 | 113 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | AEs requiring additional therapy- All grades | 186 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | AEs- All grades | 297 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | AEs- Grade ≥ 3 | 159 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | Treatment-related AEs- All grades | 221 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | Treatment-related AEs- Grade ≥ 3 | 123 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | SAEs- All grades | 54 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | SAEs- Grade ≥ 3 | 45 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | Treatment-related SAEs- All grades | 7 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | Treatment-related SAEs- Grade ≥ 3 | 6 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | Fatal SAEs- All grades | 5 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | Treatment-related Fatal SAEs- All grades | 0 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | AEs leading to discontinuation- All grades | 17 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | Treatment-related AEs leading to discontinuation- All grades | 7 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | Treatment-related AEs leading to discontinuation-Grade ≥ 3 | 4 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | AEs leading to dose adjustment/interruption- All grades | 185 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | AEs leading to dose adjustment/interruption- Grade ≥ 3 | 132 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | Treatment-related AEs leading to dose adjustment/interruption- All grades | 134 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | AEs requiring additional therapy- Grade ≥ 3 | 56 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | Treatment-related AEs requiring additional therapy- All grades | 47 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With AEs and SAEs in the Extension Phase | Treatment-related AEs requiring additional therapy- Grade ≥ 3 | 12 Participants |
Secondary
Number of Participants With Clinical Benefit (Extension Phase)
Clinical benefit as assessed by the Investigator during Extension phase
Time frame: 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
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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 1 Day 1 | 413 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 4 Day 1 | 386 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 7 Day 1 | 353 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 10 Day 1 | 323 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 13 Day 1 | 245 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 31 Day 1 | 44 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 34 Day 1 | 32 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 37 Day 1 | 24 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 16 Day 1 | 200 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 19 Day 1 | 183 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 22 Day 1 | 118 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 25 Day 1 | 55 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 28 Day 1 | 51 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | Number of Participants With Clinical Benefit (Extension Phase) | Cycle 40 Day 1 | 5 Participants |
Secondary
Overall Response Rate (ORR) Based on Investigator's Assessment (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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribociclib + Letrozole + Goserelin/Leuprolide | Overall Response Rate (ORR) Based on Investigator's Assessment (Core Phase) | 29.3 Percentage of participants |
Secondary
Time-to-Progression (TTP) Based on Investigator's Assessment (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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib + Letrozole + Goserelin/Leuprolide | Time-to-Progression (TTP) Based on Investigator's Assessment (Core Phase) | 27.1 Months |
Post Hoc
All Collected Deaths
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ribociclib + Letrozole + Goserelin/Leuprolide | All Collected Deaths | On-treatment Core Phase | 74 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | All Collected Deaths | All deaths Core Phase | 164 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | All Collected Deaths | All deaths Extension Phase | 8 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | All Collected Deaths | Post-treatment survival follow-up Core Phase | 90 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | All Collected Deaths | On-treatment Extension Phase | 5 Participants |
| Ribociclib + Letrozole + Goserelin/Leuprolide | All Collected Deaths | Post-treatment survival follow-up Extension Phase | 3 Participants |
Other Pre-specified
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
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.
Time frame: 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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 0.5 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Ribociclib + Letrozole + Goserelin/Leuprolide | 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 |
| Sensitive Cohort | 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) | -0.466 log2 transformed relative ratio | Standard Deviation 0.129 |
| Sensitive Cohort | 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) | 0.205 log2 transformed relative ratio | Standard Deviation 0.431 |
| Sensitive Cohort | 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) | -0.077 log2 transformed relative ratio | Standard Deviation 0.374 |
| Sensitive Cohort | 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) | -0.126 log2 transformed relative ratio | Standard Deviation 0.213 |
| Sensitive Cohort | 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) | -0.033 log2 transformed relative ratio | Standard Deviation 0.568 |
| Sensitive Cohort | 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) | 0.176 log2 transformed relative ratio | Standard Deviation 0.387 |
| Sensitive Cohort | 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) | -0.175 log2 transformed relative ratio | Standard Deviation 0.274 |
| Sensitive Cohort | 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) | 0.070 log2 transformed relative ratio | Standard Deviation 0.237 |
| Sensitive Cohort | 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) | -0.004 log2 transformed relative ratio | Standard Deviation 0.181 |
| Sensitive Cohort | 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) | -0.325 log2 transformed relative ratio | Standard Deviation 0.147 |
| Sensitive Cohort | 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) | -0.129 log2 transformed relative ratio | Standard Deviation 0.087 |
| Sensitive Cohort | 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) | -0.036 log2 transformed relative ratio | Standard Deviation 0.221 |
| Sensitive Cohort | 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) | -0.015 log2 transformed relative ratio | Standard Deviation 0.186 |
| Sensitive Cohort | 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) | 0.230 log2 transformed relative ratio | Standard Deviation 1.041 |
| Sensitive Cohort | 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) | 0.141 log2 transformed relative ratio | Standard Deviation 0.581 |
| Sensitive Cohort | 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) | -0.082 log2 transformed relative ratio | Standard Deviation 0.123 |
| Sensitive Cohort | 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) | 0.128 log2 transformed relative ratio | Standard Deviation 0.435 |
| Sensitive Cohort | 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) | -0.010 log2 transformed relative ratio | Standard Deviation 0.198 |
| Sensitive Cohort | 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) | -0.074 log2 transformed relative ratio | Standard Deviation 0.136 |
| Sensitive Cohort | 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) | 0.051 log2 transformed relative ratio | Standard Deviation 0.393 |
| Sensitive Cohort | 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) | -0.144 log2 transformed relative ratio | Standard Deviation 0.205 |
| Sensitive Cohort | 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) | 0.170 log2 transformed relative ratio | Standard Deviation 0.274 |
| Sensitive Cohort | 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) | 0.169 log2 transformed relative ratio | Standard Deviation 0.662 |
| Sensitive Cohort | 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) | 0.184 log2 transformed relative ratio | Standard Deviation 0.375 |
| Sensitive Cohort | 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) | -0.080 log2 transformed relative ratio | Standard Deviation 0.166 |
| Sensitive Cohort | 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) | -0.151 log2 transformed relative ratio | Standard Deviation 0.27 |
| Sensitive Cohort | 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) | 0.038 log2 transformed relative ratio | Standard Deviation 0.284 |
| Sensitive Cohort | 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) | 0.043 log2 transformed relative ratio | Standard Deviation 0.145 |
| Sensitive Cohort | 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) | 0.010 log2 transformed relative ratio | Standard Deviation 0.399 |
| Sensitive Cohort | 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) | -0.218 log2 transformed relative ratio | Standard Deviation 0.352 |
| Sensitive Cohort | 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) | 0.075 log2 transformed relative ratio | Standard Deviation 0.271 |
| Sensitive Cohort | 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) | 0.050 log2 transformed relative ratio | Standard Deviation 0.221 |
| Sensitive Cohort | 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) | 0.094 log2 transformed relative ratio | Standard Deviation 0.194 |