Breast Cancer
Conditions
Keywords
HR-positive, HER2-negative, advanced breast cancer, Ribociclib, NSAI, Goserelin, Docetaxel / capecitabine, Paclitaxel/gemcitabine, Capecitabine/vinorelbine, CDK4/6 inhibitors, Phase II, ER-positive, PR-positive, Premenopausal, Perimenopausal
Brief summary
To compare the combination of Ribociclib plus goserelin acetate with hormonal therapy versus combination chemotherapy in premenopausal or perimenopausal patients with advanced or metastatic breast cancer
Detailed description
Patients were randomly assigned to one of the below treatment arms in 1:1 ratio: * Ribociclib arm: non-steroidal aromatase inhibitor (NSAI) + goserelin + Ribociclib * Combination chemotherapy arm: Either of docetaxel + capecitabine, paclitaxel + gemcitabine, or capecitabine + vinorelbine based chemotherapy treatment Randomization was stratified by (1) the presence of liver metastases (present or absent) (2) disease-free interval (DFI) \< 2 years (yes or no, de novo stage 4 was defined as DFI \> 2 years). The study consisted of a 28-day Screening phase, treatment phase (including end of treatment (EOT) visit and safety follow-up), and survival follow-up. Patients received study treatment until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason. Patients were followed for survival regardless of treatment discontinuation for any reason (except if consent was withdrawn, patient was lost to follow-up, or until death) and regardless of achieving the primary endpoint, until death, withdrawal of consent, or loss to follow-up.
Interventions
COMBINATION_PRODUCTDocetaxel / Capecitabine
Docetaxel (IV Infusion) / Capecitabine (Tablets for oral use): Docetaxel once, on day 1 of the 3-weeks cycle. Capecitabine twice daily, on Days 1 to 14, followed by a 1-week rest period, in 3 weeks cycle. Docetaxel (60 - 75 mg/m²)/capecitabine (1600 - 2500 mg/m²/day)
COMBINATION_PRODUCTCapecitabine / Vinorelbine
Capecitabine (Tablets for oral use) / Vinorelbine (Capsule for Oral use/IV infusion ). Capecitabine twice daily on day 1 to 14, followed by a 1-week rest period, in 3 weeks cycle. Vinorelbine, once, on Day 1 and Day 8 in 3 weeks cycles. Capecitabine (1600 - 2500 mg/m2/day)/vinorelbine (60 to 80 mg/m2/day \[oral\] or (25 to 30 mg/m2 \[IV infusion\]
COMBINATION_PRODUCTPaclitaxel / Gemcitabine
Paclitaxel (IV Infusion) / Gemcitabine (IV Infusion): Paclitaxel via 3-hour intravenous (IV) infusion on Day 1 in 3-weeks cycles, OR Paclitaxel via 1 hour intravenous (IV) infusion on Day 1 and day 8- in 3-weeks cycles. Gemcitabine at via 30 minute IV infusion on Day 1 and Day 8 in 3 weeks cycles. Paclitaxel (175 mg/m2) (on Day 1 in 3-weeks cycles)/ gemcitabine (1000 - 1250 mg/m2) OR Paclitaxel (80 - 90 mg/m2) (on Day 1 and Day 8 in 3-weeks cycles) / gemcitabine (800 - 1250 mg/m2)
DRUGRibociclib
Dose: 600 mg (200 mg \* 3) Days 1 to 21 of each 28 day cycle Tablets for oral use
Letrozole: Dose: 2.5 mg All days of every cycle without interruption). Tablets for oral use Anastrozole: dose: 1 mg All days of every cycle without interruption. Tablets for oral use The NSAI (letrozole or anastrozole) will be decided by the treating physician.
DRUGGoserelin
Dose: 3.6 mg Day 1 of each 28 day cycle (regardless of ribociclib treatment cycle) with an administration window of + 3 days. Subcutaneous implant
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This was a randomized, phase II, open label, multi-center trial comparing the combination of NSAI (letrozole or anastrozole) + goserelin + ribociclib versus combination chemotherapy (either of docetaxel/capecitabine or paclitaxel/gemcitabine or capecitabine/vinorelbine). Premenopausal or perimenopausal women with HR+, HER2- negative, advanced breast cancer with ECOG performance status of 0 to 2 and having symptomatic visceral metastases, or rapid progression of disease or impending visceral compromise, or markedly symptomatic non visceral disease were considered for this study.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 59 Years
Healthy volunteers
No
Inclusion criteria
1. Patient was an adult female ≥ 18 years old and \< 60 years old at the time of informed consent. 2. Patient had a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer based on the most recently analyzed tissue sample and all tested by local laboratory. ER should have been more than 10% ER positive or Allred ≥5 by local laboratory testing. 3. 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 and based on the most recently analyzed tissue sample. 4. Women with inoperable locally advanced or metastatic breast cancer not amenable to curative therapy. Patients had to fulfill at least one of the following criteria to be considered that combination chemotherapy was needed according to PI's judgment. However, for patients who were eligible under inoperable locally advanced breast cancer or criteria 4c, the recruitment was stopped to enrich patient population with visceral metastases. * Symptomatic visceral metastases * Rapid progression of disease or impending visceral compromise. * Markedly symptomatic non-visceral disease if the treating physician opted to give chemotherapy for rapid palliation of patient's symptoms. 5. Patient was premenopausal or perimenopausal at the time of study entry. 1. Premenopausal status was defined as either: * Patient had last menstrual period within the last 12 months. OR * If on tamoxifen within the past 14 days, plasma estradiol and FSH were in the premenopausal range, according to local laboratory definition. * In case of therapy induced amenorrhea, plasma estradiol and/or FSH were in the premenopausal range according to local laboratory definition. * Patients who had undergone bilateral oophorectomy were not eligible. 2. Perimenopausal status was defined as neither premenopausal nor postmenopausal. 6. Patients had received neither prior hormonal therapy nor chemotherapy for advanced breast cancer, except LHRH agonist. Patients who received ≤ 14 days of tamoxifen or a NSAI (letrozole or anastrozole) with or without LHRH agonist for advanced breast cancer prior to randomization were eligible. Patient had measurable disease.
Exclusion criteria
; 1. Patient received prior systemic anti-cancer therapy (including hormonal therapy and chemotherapy, or any CDK4/6 inhibitor for advanced breast cancer). * Patients who received (neo) adjuvant therapy for breast cancer were eligible. If the prior neo (adjuvant) therapy included aromatase inhibitors, the treatment-free interval must have been greater than 12 months from the completion of aromatase inhibitor treatment until randomization. * If patients had disease recurrence during adjuvant tamoxifen treatment, disease-free interval (defined as duration between the date of patient received complete tumor resection for primary breast cancer lesion to the date of disease recurrence documented) must have been greater than 12 months. * Patients who were receiving ≤ 14 days of tamoxifen or NSAI or LHRH agonists ≤ 28 days for advanced breast cancer prior to randomization were eligible. 2. Patient had received extended-field radiotherapy ≤ 2 weeks prior to randomization or limited field radiotherapy ≤ 2 weeks prior to randomization, and had not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion). Patient from whom ≥ 25% of the bone marrow had been previously irradiated were also excluded. 3. Patient had a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated, basal or squamous cell skin carcinoma or curatively resected cervical cancer in situ. 4. Patients who had lung metastases with oxygen demand in resting status. 5. Patients who had liver metastases with bilirubin \> 1.5 ULN. 6. Patients with CNS involvement unless they met ALL of the following criteria: * At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment. * Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases. * Leptomeningeal metastases was not allowed, even with stable clinical condition.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Up to approximately 34 months | Progression-free survival was defined as the time from the date of randomization to the date of the first documented progression as per local review and according to RECIST 1.1 or death due to any cause. PFS was censored at the date of the last adequate tumor assessment if no PFS event was observed at the time of last patient, last visit (LPLV). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 3-month Treatment Failure Rate | Up to approximately 3 months | Treatment failure rate was defined as the percentage of patients who discontinued the study treatment due to progressive disease, death due to any cause, change to other anti-cancer therapy, or discontinuation due to reasons other than protocol violation or administrative problems. |
| Overall Response Rate (ORR) | Up to approximately 34 months | Overall response rate (ORR) was defined as the percentage of patients with a best overall response (BOR) of complete response (CR) or partial response (PR, response without image confirmation), as per local review and according to RECIST 1.1. |
| Clinical Benefit Rate | Up to approximately 34 months | Clinical benefit rate was defined as the percentage of patients with a BOR of CR, PR, or stable disease (SD, response without image confirmation) lasting 24 weeks or longer, as defined by RECIST 1.1. |
| Time to Response | Up to approximately 34 months | Time to response was defined as the time from the date of randomization to the first documented response of either CR or PR, which must be subsequently confirmed, as defined by RECIST 1.1. Patients who did not achieve a confirmed PR or CR were censored at: the maximum follow-up time (i.e., LPLV - FPFV used for the analysis) for patients who had a PFS event (i.e., either progressed or died due to any cause); the last adequate tumor assessment date for all other patients. |
| Time to Treatment Failure | Up to approximately 34 months | Time to treatment failure was defined as the time from the date of randomization/start of treatment to the earliest of date of progression, date of death due to any cause, change to other anti-cancer therapy, or date of discontinuation due to reasons other than 'Protocol violation' or 'Administrative problems'. Patients who did not achieve a confirmed PR or CR were censored at: the maximum follow-up time (i.e., LPLV - first patient first visit \[FPFV\] used for the analysis) for patients who had a PFS event (i.e., either progressed or died due to any cause); the last adequate tumor assessment date for all other patients. |
| Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Up to approximately 46 months | FACT-B is a self-reported 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. |
| Number of Patients With Adverse Events, Categorized by Severity | Up to approximately 46 months | Adverse events were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 or higher. If CTCAE grading did not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, were used. A patient with multiple severity grades for an AE was only counted under the maximum grade. Data for Grades 3 and 4 are reported. |
| Number of Patients With Laboratory Abnormalities | Up to approximately 46 months | Grading of laboratory values was assigned programmatically as per NCI Common Terminology Criteria for Adverse Events (CTCAE) version available at the time of analysis. The calculation of CTCAE grades was based on the observed laboratory values only, clinical assessments were not be taken into account. CTCAE Grade 0 was assigned for all non-missing values not graded as 1 or higher. Grade 5 was not used. For laboratory tests where grades were not defined by CTCAE available at the time of analysis, results were categorized as low/normal/high based on laboratory normal ranges. |
| Post-Hoc: All Collected Deaths | On-treatment deaths: Up to approximately 46 months. Post-treatment survival follow-up deaths: Up to approximately 2 additional months. | On-treatment deaths due to any cause were collected from first dose of study medication to 30 days after the last dose of study treatment. Post-treatment survival follow-up deaths were collected from day 31 after last dose of study medication to end of study. |
| Overall Survival (OS) | Up to approximately 46 months | Overall survival was defined as the time from the date of randomization to the date of death due to any cause. If a patient was not known to have died at the time of LPLV, then OS was censored at the last contact date. |
Countries
Egypt, India, Jordan, Lebanon, Malaysia, Russia, Saudi Arabia, Singapore, South Africa, Taiwan, Thailand, Turkey (Türkiye), Vietnam
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ribociclib 600 mg Combination of non-steroidal aromatase inhibitor: NSAI (letrozole or anastrozole) + goserelin + ribociclib.
1. Ribociclib (600 mg) was dosed orally for the first 21 days out of a 28-day cycle.
2. Letrozole (2.5 mg) or anastrozole (1 mg) were dosed orally daily (28 days out of the 28-day cycle).
3. Goserelin (3.6 mg) was continuously released via a subcutaneous implant injected on Day 1 of each 28-day cycle (regardless of ribociclib treatment cycle) with an administration window of + 3 days. | 112 |
| Combination Chemotherapy Combination chemotherapies of docetaxel/capecitabine, paclitaxel/gemcitabine or capecitabine/vinorelbine were administered to patients enrolled in the control group. The chemotherapy regimen was decided by the treating physician. | 110 |
| Total | 222 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 4 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Not Treated | 0 | 10 |
| Overall Study | Physician Decision | 1 | 5 |
| Overall Study | Progressive Disease (PD) | 65 | 65 |
| Overall Study | Subject Decision | 2 | 9 |
Baseline characteristics
| Characteristic | Ribociclib 600 mg | Combination Chemotherapy | Total |
|---|---|---|---|
| Age, Continuous | 42.9 years STANDARD_DEVIATION 6.26 | 42.0 years STANDARD_DEVIATION 6.72 | 42.5 years STANDARD_DEVIATION 6.49 |
| Height | 157.50 cm STANDARD_DEVIATION 7.489 | 158.34 cm STANDARD_DEVIATION 6.548 | 157.92 cm STANDARD_DEVIATION 7.035 |
| Race/Ethnicity, Customized Asian | 60 participants | 58 participants | 118 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 108 participants | 108 participants | 216 participants |
| Race/Ethnicity, Customized Not Reported | 3 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized White | 51 participants | 52 participants | 103 participants |
| Sex/Gender, Customized Female | 112 participants | 110 participants | 222 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 112 | 0 / 100 | 29 / 107 | 29 / 92 |
| other Total, other adverse events | 112 / 112 | 100 / 100 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 17 / 112 | 16 / 100 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Progression-free Survival
Progression-free survival was defined as the time from the date of randomization to the date of the first documented progression as per local review and according to RECIST 1.1 or death due to any cause. PFS was censored at the date of the last adequate tumor assessment if no PFS event was observed at the time of last patient, last visit (LPLV).
Time frame: Up to approximately 34 months
Population: The full analysis set comprised all patients to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib 600 mg | Progression-free Survival | 21.8 months |
| Combination Chemotherapy | Progression-free Survival | 12.8 months |
p-value: 0.00395% CI: [0.429, 0.87]one-sided stratified logrank test
Secondary
3-month Treatment Failure Rate
Treatment failure rate was defined as the percentage of patients who discontinued the study treatment due to progressive disease, death due to any cause, change to other anti-cancer therapy, or discontinuation due to reasons other than protocol violation or administrative problems.
Time frame: Up to approximately 3 months
Population: The full analysis set comprised all patients to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribociclib 600 mg | 3-month Treatment Failure Rate | 11.6 percentage of participants |
| Combination Chemotherapy | 3-month Treatment Failure Rate | 21.8 percentage of participants |
p-value: 0.02Cochran-Mantel-Haenszel
Secondary
Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire
FACT-B is a self-reported 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.
Time frame: Up to approximately 46 months
Population: The full analysis set comprised all patients to whom study treatment was assigned by randomization. Results are reported for participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 6 n=109,90 | 4.3 score on a scale | Standard Deviation 13.45 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 12 n=100,82 | 5.5 score on a scale | Standard Deviation 16.28 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 20 n=94,76 | 5.9 score on a scale | Standard Deviation 18.18 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 28 n=87,67 | 7.9 score on a scale | Standard Deviation 17.54 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 36 n=79,56 | 7.3 score on a scale | Standard Deviation 18.65 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 44 n=75,50 | 7.2 score on a scale | Standard Deviation 18.33 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 56 n=68,38 | 7.3 score on a scale | Standard Deviation 20.79 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 68 n=64,32 | 7.4 score on a scale | Standard Deviation 19.86 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 80 n=53,22 | 7.1 score on a scale | Standard Deviation 25.49 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 92 n=45,16 | 9.4 score on a scale | Standard Deviation 22.46 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 104 n=36,12 | 7.9 score on a scale | Standard Deviation 22.26 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 116 n=29,8 | 5.3 score on a scale | Standard Deviation 23.58 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 128 n=26,8 | 2.8 score on a scale | Standard Deviation 24.17 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 140 n=21,6 | 10.9 score on a scale | Standard Deviation 24.3 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 152 n=17,5 | 3.6 score on a scale | Standard Deviation 20.39 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 164 n=10,1 | 1.6 score on a scale | Standard Deviation 16.56 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 176 n=3,1 | 16.9 score on a scale | Standard Deviation 31.39 |
| Ribociclib 600 mg | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 188 n=1,0 | 7.0 score on a scale | — |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 6 n=109,90 | 4.8 score on a scale | Standard Deviation 15.33 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 176 n=3,1 | 39.7 score on a scale | — |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 12 n=100,82 | 4.4 score on a scale | Standard Deviation 16.73 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 92 n=45,16 | 9.6 score on a scale | Standard Deviation 20.24 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 20 n=94,76 | 4.9 score on a scale | Standard Deviation 17.51 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 140 n=21,6 | 20.8 score on a scale | Standard Deviation 13.8 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 28 n=87,67 | 6.2 score on a scale | Standard Deviation 16.15 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 104 n=36,12 | 15.1 score on a scale | Standard Deviation 13.04 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 36 n=79,56 | 6.5 score on a scale | Standard Deviation 16.6 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 164 n=10,1 | 33.8 score on a scale | — |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 44 n=75,50 | 6.6 score on a scale | Standard Deviation 14.39 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 116 n=29,8 | 15.8 score on a scale | Standard Deviation 7.92 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 56 n=68,38 | 4.7 score on a scale | Standard Deviation 16.13 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 152 n=17,5 | 17.0 score on a scale | Standard Deviation 14.06 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 68 n=64,32 | 5.1 score on a scale | Standard Deviation 16.92 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 128 n=26,8 | 17.0 score on a scale | Standard Deviation 11.4 |
| Combination Chemotherapy | Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire | Week 80 n=53,22 | 7.0 score on a scale | Standard Deviation 14.5 |
Secondary
Clinical Benefit Rate
Clinical benefit rate was defined as the percentage of patients with a BOR of CR, PR, or stable disease (SD, response without image confirmation) lasting 24 weeks or longer, as defined by RECIST 1.1.
Time frame: Up to approximately 34 months
Population: The full analysis set comprised all patients to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribociclib 600 mg | Clinical Benefit Rate | 81.3 percentage of participants |
| Combination Chemotherapy | Clinical Benefit Rate | 74.5 percentage of participants |
p-value: 0.116Cochran-Mantel-Haenszel
Secondary
Number of Patients With Adverse Events, Categorized by Severity
Adverse events were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 or higher. If CTCAE grading did not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, were used. A patient with multiple severity grades for an AE was only counted under the maximum grade. Data for Grades 3 and 4 are reported.
Time frame: Up to approximately 46 months
Population: The safety set included all patients who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ribociclib 600 mg | Number of Patients With Adverse Events, Categorized by Severity | All grades | 112 Participants |
| Ribociclib 600 mg | Number of Patients With Adverse Events, Categorized by Severity | Grade 3 | 71 Participants |
| Ribociclib 600 mg | Number of Patients With Adverse Events, Categorized by Severity | Grade 4 | 18 Participants |
| Combination Chemotherapy | Number of Patients With Adverse Events, Categorized by Severity | All grades | 100 Participants |
| Combination Chemotherapy | Number of Patients With Adverse Events, Categorized by Severity | Grade 3 | 62 Participants |
| Combination Chemotherapy | Number of Patients With Adverse Events, Categorized by Severity | Grade 4 | 11 Participants |
Secondary
Number of Patients With Laboratory Abnormalities
Grading of laboratory values was assigned programmatically as per NCI Common Terminology Criteria for Adverse Events (CTCAE) version available at the time of analysis. The calculation of CTCAE grades was based on the observed laboratory values only, clinical assessments were not be taken into account. CTCAE Grade 0 was assigned for all non-missing values not graded as 1 or higher. Grade 5 was not used. For laboratory tests where grades were not defined by CTCAE available at the time of analysis, results were categorized as low/normal/high based on laboratory normal ranges.
Time frame: Up to approximately 46 months
Population: The safety set included all patients who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Lymphocytes (absolute) - Hypo: Grade 3 | 21 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Lymphocytes (absolute) - Hypo: Grade 4 | 1 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Leukocytes - Hypo: Grade 4 | 0 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Neutrophils (absolute) - Hypo: Grades 1/2 | 40 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Hemoglobin - Hypo: Grade 3 | 5 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Neutrophils (absolute) - Hypo: Grade 3 | 55 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Lymphocytes (absolute) - Hyper: Grades 1/2 | 3 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Neutrophils (absolute) - Hypo: Grade 4 | 10 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Leukocytes - Hypo: Grades 1/2 | 71 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Platelets - Hypo: Grades 1/2 | 37 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Lymphocytes (absolute) - Hyper: Grade 3 | 0 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Platelets - Hypo: Grade 3 | 2 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Hemoglobin - Hypo: Grades 1/2 | 82 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Platelets - Hypo: Grade 4 | 1 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Lymphocytes (absolute) - Hyper: Grade 4 | 0 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Prothrombin Intl. Normalized Ratio - Hyper: Grades 1/2 | 0 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Leukocytes - Hypo: Grade 3 | 34 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Prothrombin Intl. Normalized Ratio - Hyper: Grade 3 | 0 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Lymphocytes (absolute) - Hypo: Grades 1/2 | 55 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Prothrombin Intl. Normalized Ratio - Hyper: Grade 4 | 0 Participants |
| Ribociclib 600 mg | Number of Patients With Laboratory Abnormalities | Hemoglobin - Hypo: Grade 4 | 0 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Prothrombin Intl. Normalized Ratio - Hyper: Grade 4 | 0 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Hemoglobin - Hypo: Grades 1/2 | 73 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Hemoglobin - Hypo: Grade 3 | 11 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Hemoglobin - Hypo: Grade 4 | 0 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Leukocytes - Hypo: Grades 1/2 | 54 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Leukocytes - Hypo: Grade 3 | 8 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Leukocytes - Hypo: Grade 4 | 1 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Lymphocytes (absolute) - Hyper: Grades 1/2 | 10 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Lymphocytes (absolute) - Hyper: Grade 3 | 0 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Lymphocytes (absolute) - Hyper: Grade 4 | 0 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Lymphocytes (absolute) - Hypo: Grades 1/2 | 37 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Lymphocytes (absolute) - Hypo: Grade 4 | 4 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Neutrophils (absolute) - Hypo: Grades 1/2 | 35 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Neutrophils (absolute) - Hypo: Grade 3 | 23 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Neutrophils (absolute) - Hypo: Grade 4 | 9 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Platelets - Hypo: Grades 1/2 | 27 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Platelets - Hypo: Grade 3 | 2 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Platelets - Hypo: Grade 4 | 1 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Prothrombin Intl. Normalized Ratio - Hyper: Grades 1/2 | 8 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Prothrombin Intl. Normalized Ratio - Hyper: Grade 3 | 0 Participants |
| Combination Chemotherapy | Number of Patients With Laboratory Abnormalities | Lymphocytes (absolute) - Hypo: Grade 3 | 3 Participants |
Secondary
Overall Response Rate (ORR)
Overall response rate (ORR) was defined as the percentage of patients with a best overall response (BOR) of complete response (CR) or partial response (PR, response without image confirmation), as per local review and according to RECIST 1.1.
Time frame: Up to approximately 34 months
Population: The full analysis set comprised all patients to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribociclib 600 mg | Overall Response Rate (ORR) | 66.1 percentage of participants |
| Combination Chemotherapy | Overall Response Rate (ORR) | 61.8 percentage of participants |
p-value: 0.255Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS)
Overall survival was defined as the time from the date of randomization to the date of death due to any cause. If a patient was not known to have died at the time of LPLV, then OS was censored at the last contact date.
Time frame: Up to approximately 46 months
Population: The full analysis set comprised all patients to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib 600 mg | Overall Survival (OS) | NA months |
| Combination Chemotherapy | Overall Survival (OS) | NA months |
Secondary
Post-Hoc: All Collected Deaths
On-treatment deaths due to any cause were collected from first dose of study medication to 30 days after the last dose of study treatment. Post-treatment survival follow-up deaths were collected from day 31 after last dose of study medication to end of study.
Time frame: On-treatment deaths: Up to approximately 46 months. Post-treatment survival follow-up deaths: Up to approximately 2 additional months.
Population: All participants to whom study treatment was assigned.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ribociclib 600 mg | Post-Hoc: All Collected Deaths | On-treatment deaths | 5 Participants |
| Ribociclib 600 mg | Post-Hoc: All Collected Deaths | Post-treatment survival follow-up deaths | 29 Participants |
| Ribociclib 600 mg | Post-Hoc: All Collected Deaths | All deaths | 34 Participants |
| Combination Chemotherapy | Post-Hoc: All Collected Deaths | On-treatment deaths | 0 Participants |
| Combination Chemotherapy | Post-Hoc: All Collected Deaths | Post-treatment survival follow-up deaths | 29 Participants |
| Combination Chemotherapy | Post-Hoc: All Collected Deaths | All deaths | 29 Participants |
Secondary
Time to Response
Time to response was defined as the time from the date of randomization to the first documented response of either CR or PR, which must be subsequently confirmed, as defined by RECIST 1.1. Patients who did not achieve a confirmed PR or CR were censored at: the maximum follow-up time (i.e., LPLV - FPFV used for the analysis) for patients who had a PFS event (i.e., either progressed or died due to any cause); the last adequate tumor assessment date for all other patients.
Time frame: Up to approximately 34 months
Population: The full analysis set comprised all patients to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib 600 mg | Time to Response | 4.9 months |
| Combination Chemotherapy | Time to Response | 3.2 months |
95% CI: [0.546, 1.064]
Secondary
Time to Treatment Failure
Time to treatment failure was defined as the time from the date of randomization/start of treatment to the earliest of date of progression, date of death due to any cause, change to other anti-cancer therapy, or date of discontinuation due to reasons other than 'Protocol violation' or 'Administrative problems'. Patients who did not achieve a confirmed PR or CR were censored at: the maximum follow-up time (i.e., LPLV - first patient first visit \[FPFV\] used for the analysis) for patients who had a PFS event (i.e., either progressed or died due to any cause); the last adequate tumor assessment date for all other patients.
Time frame: Up to approximately 34 months
Population: The full analysis set comprised all patients to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ribociclib 600 mg | Time to Treatment Failure | 18.6 months |
| Combination Chemotherapy | Time to Treatment Failure | 9.1 months |
95% CI: [0.363, 0.68]