HER-2 Positive Breast Cancer, Hormone Receptor Positive Breast Cancer
Conditions
Brief summary
The purpose of this study is to evaluate the effectiveness of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus physicians choice standard of care chemotherapy in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 positive (HER2+) locally advanced or metastatic breast cancer after prior exposure to at least two HER2-directed therapies for advanced disease.
Interventions
DRUGAbemaciclib
Administered Orally
DRUGTrastuzumab
Administered IV
DRUGFulvestrant
Administered IM
DRUGStandard of Care Single Agent Chemotherapy
Standard-of-care single-agent chemotherapy of physician's choice administered according to product label
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* diagnosis of HR+, HER2+ breast cancer (BC) * unresectable locally advanced recurrent BC or metastatic BC * adequate tumor tissue available prior to randomization * measurable and/or non-measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 * previously received: * at least 2 HER2-directed therapies for advanced disease * participant must have received trastuzumab emtansine (T-DM1) in any disease setting * must have received a taxane in any disease setting * may have received any endocrine therapy (excluding fulvestrant) * have postmenopausal status due to surgical / natural menopause or chemical ovarian suppression * performance status (PS) of 0 to 1 on the Eastern Cooperative Oncology Group scale * left ventricular ejection fraction (LVEF) of 50% or higher at baseline * adequate organ function * negative serum pregnancy test at baseline (within 14 days prior to randomization) and agree to use medically approved precautions to prevent pregnancy during the study and for 12 weeks following the last dose of abemaciclib if menopause induced by gonadotropin-releasing hormone (GnRH) agonist or radiation * discontinued previous localized radiotherapy for palliative purposes or for lytic lesions at risk of fracture at least 2 weeks prior to randomization and recovered from the acute effects of therapy * discontinued all previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, and endocrine therapy), except trastuzumab, for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving study drug, and recovered from the acute effects of therapy * are able to swallow capsules
Exclusion criteria
* have visceral crisis * known central nervous system (CNS) metastases that are untreated, symptomatic, or require steroids to control symptoms * had major surgery within 14 days prior to randomization * received prior treatment with any cyclin-dependent kinase (CDK) 4 and CDK 6 inhibitor * received treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of randomization for a nonmyelosuppressive or myelosuppressive agent, respectively * have serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study * history within the last 6 months of symptomatic congestive heart failure, myocardial infarction, or unstable angina * history within the last 12 months of any of the following conditions: syncope of cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest * history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission with no therapy for a minimum of 3 years * active bacterial, fungal infection, or detectable viral infection * have received any recent (within 28 days prior to randomization) live virus vaccination * hypersensitivity to trastuzumab, murine proteins, fulvestrant, or to any of the excipients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Baseline to Progressive Disease or Death from Any Cause (Up To 36 Months) | PFS time was measured from the date of randomization to the date of investigator-determined objective progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of first dose, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With 2 Year OS | Randomization to date of death from any cause assessed at 2 years | OS is defined as the time from the date of randomization until death from any cause. For participants not known to have died by the data-inclusion cutoff date, OS is censored at the last date they were known to be alive. For each treatment arm OS rate at 2 years from the date of randomization was determined using the OS times and was estimated using the Kaplan-Meier method. |
| Percentage of Participants With 3 Year OS | Randomization to date of death from any cause assessed at 3 years | OS is defined as the time from the date of randomization until death from any cause. For participants not known to have died by the data-inclusion cutoff date, OS is censored at the last date they were known to be alive. For each treatment arm OS rate at 3 years from the date of randomization was determined using the OS times and was estimated using the Kaplan-Meier method. |
| Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) | Baseline to Objective Disease Progression (Up To 36 Months) | ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. |
| Duration of Response (DoR) | Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (Up To 36 Months) | DoR was the time from the date of first evidence of complete response or partial response to the date of objective progression or the date of death due to any cause, whichever is earlier. CR and PR were defined using the RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. If a responder was not known to have died or have objective progression as of the data inclusion cutoff date, duration of response was censored at the last adequate tumor assessment date. |
| Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) | Baseline to Objective Disease Progression (Up To 36 Months) | Disease Control Rate (DCR) was the percentage of participants with a best overall response of CR, PR, or Stable Disease (SD) as per Response using RECIST v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. |
| Percentage of Participants With 1 Year Overall Survival (OS) | Randomization to date of death from any cause assessed at 1 year | OS is defined as the time from the date of randomization until death from any cause. For participants not known to have died by the data-inclusion cutoff date, OS is censored at the last date they were known to be alive. For each treatment arm OS rate at 1 year from the date of randomization was determined using the OS times and was estimated using the Kaplan-Meier method. |
| Change From Baseline in Pain and Symptom Burden Assessment on the Modified Brief Pain Inventory-Short Form (mBPI-sf) | Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months) | The mBPI-sf is an 11-item instrument used as a multiple-item measure of cancer pain intensity. In addition to pain intensity (4 items), the mBPI-sf is designed for participants to record the presence of pain in general, pain relief, and pain interference with function (general activity, mood, ability to walk, ability to perform normal work, relations with others, sleep, enjoyment of life). Responses for the mBPI-sf items are captured through the use of 11-point numeric rating scales anchored at 0 (no pain or does not interfere) and 10 (pain as bad as you can imagine or completely interferes). The mBPI-sf recall period is 24 hours and typical completion time for this instrument is less than 5 minutes. Mean Interference Score data is reported here. Least square (LS) Mean value was controlled for Treatment, visit, Treatment\*Visit and baseline. |
| Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months) | EORTC QLQ-C30 v3.0 was a self-administered questionnaire with multidimensional scales that measures 5 functional domains (physical, role, cognitive, emotional, and social), global health status, and symptom scales of fatigue, pain, nausea and vomiting, dyspnea, loss of appetite, insomnia, constipation and diarrhea, and financial difficulties. A linear transformation is applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For functional domains and global health status, higher scores represent a better level of functioning. For symptoms scales, higher scores represented a greater degree of symptoms. LS Mean value was controlled for Treatment, visit, Treatment\*Visit and baseline. |
| Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score | Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months) | The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status. Participants completed the 5-level (no problem, slight problem, moderate problem, severe problem, and inability or extreme problem), 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire concerning their current health state. Five dimensions of health status are each assessed with 5 response options and scored as a composite index which were anchored on a scale of 0 to 1 with a higher score representing better health status.LS Mean value was controlled for Treatment, visit, Treatment\*Visit and baseline. |
| Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) | Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months) | European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) is a standardized measure of health status of the participant. The EQ-5D-5L is assessed using a visual analog scale (VAS) that ranged from 0 to 100 millimeter (mm), where 0 is the worst health you can imagine and 100 is the best health you can imagine. A higher score indicates better health state. LS Mean value was controlled for Treatment, visit, Treatment\*Visit and baseline. |
| Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20) | Cycle(C)1 Day(D)1,C1D15, C2D1, C2D8, C3D1,C3D15, C4D1, C5D1:pre-dose; C1D1, C2D1, C3D1, C4D1, C5D1:post-dose | Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20) was evaluated. M2 and M20 are 2 major active metabolites of abemaciclib. |
| Percentage of Participants With Best Overall Response of CR, PR, or SD With Duration of SD for at Least 6 Months: Clinical Benefit Rate (CBR) | Date of CR, PR or SD to 6 Months Post CR, PR or SD (Up To 36 Months) | Clinical benefit rate defined as percentage of participants with best overall response of CR, PR, or SD with a duration of at least 6 months. CR, PR, or SD were defined using RECIST, v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. Percentage of participants = (participants with CR+PR+SD with a duration of at least 6 months /number of participants enrolled) \*100. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, France, Germany, Greece, Italy, Mexico, South Korea, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Completers included participants who either died due to any cause or were alive and on the study at the conclusion but off treatment.
Participants by arm
| Arm | Count |
|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle; plus 8 mg/kg trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle; plus 500 mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter. | 79 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab 150 mg abemaciclib given orally Q12H of a 21-day cycle; plus 8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle. | 79 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy 8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle plus standard of care single agent chemotherapy of physician's choice administered according to product label. | 79 |
| Total | 237 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 4 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 4 | 2 |
Baseline characteristics
| Characteristic | 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | 150 mg Abemaciclib + 8 mg/kg Trastuzumab | 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Total |
|---|---|---|---|---|
| Age, Continuous | 54.34 years STANDARD_DEVIATION 10.25 | 54.99 years STANDARD_DEVIATION 11.08 | 56.77 years STANDARD_DEVIATION 12.37 | 55.37 years STANDARD_DEVIATION 11.27 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 11 Participants | 12 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 58 Participants | 52 Participants | 56 Participants | 166 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 16 Participants | 11 Participants | 34 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 15 Participants | 10 Participants | 10 Participants | 35 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 13 Participants | 8 Participants | 27 Participants |
| Race (NIH/OMB) White | 55 Participants | 53 Participants | 55 Participants | 163 Participants |
| Region of Enrollment Argentina | 9 Participants | 7 Participants | 3 Participants | 19 Participants |
| Region of Enrollment Australia | 2 Participants | 4 Participants | 2 Participants | 8 Participants |
| Region of Enrollment Belgium | 5 Participants | 7 Participants | 7 Participants | 19 Participants |
| Region of Enrollment Brazil | 3 Participants | 1 Participants | 4 Participants | 8 Participants |
| Region of Enrollment Canada | 2 Participants | 4 Participants | 4 Participants | 10 Participants |
| Region of Enrollment France | 6 Participants | 13 Participants | 8 Participants | 27 Participants |
| Region of Enrollment Germany | 1 Participants | 2 Participants | 4 Participants | 7 Participants |
| Region of Enrollment Greece | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Italy | 2 Participants | 5 Participants | 2 Participants | 9 Participants |
| Region of Enrollment Mexico | 2 Participants | 1 Participants | 3 Participants | 6 Participants |
| Region of Enrollment South Korea | 11 Participants | 9 Participants | 10 Participants | 30 Participants |
| Region of Enrollment Spain | 6 Participants | 8 Participants | 3 Participants | 17 Participants |
| Region of Enrollment United Kingdom | 9 Participants | 9 Participants | 10 Participants | 28 Participants |
| Region of Enrollment United States | 20 Participants | 8 Participants | 17 Participants | 45 Participants |
| Sex: Female, Male Female | 79 Participants | 79 Participants | 79 Participants | 237 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 52 / 78 | 55 / 77 | 53 / 72 |
| other Total, other adverse events | 76 / 78 | 75 / 77 | 68 / 72 |
| serious Total, serious adverse events | 24 / 78 | 15 / 77 | 14 / 72 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS time was measured from the date of randomization to the date of investigator-determined objective progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of first dose, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date.
Time frame: Baseline to Progressive Disease or Death from Any Cause (Up To 36 Months)
Population: All enrolled participants. Censored participants: Abemaciclib + Trastuzumab + Fulvestrant=23; Abemaciclib + Trastuzumab = 18 and Trastuzumab + Standard of Care Chemotherapy = 27.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Progression Free Survival (PFS) | 8.3 Months |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Progression Free Survival (PFS) | 5.7 Months |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Progression Free Survival (PFS) | 5.7 Months |
Comparison: PFS analysis was planned after approximately 165 PFS events occurred in the enrolled population, yielding greater than or equal to (≥) 80% power assuming a Hazard ration (HR) of 0·667 at an experiment-wise 2-sided alpha level of 0·2.p-value: 0.0506Log Rank
Comparison: PFS analysis was planned after approximately 165 PFS events occurred in the enrolled population, yielding greater than or equal to (≥) 80% power assuming a Hazard ration (HR) of 0·667 at an experiment-wise 2-sided alpha level of 0·2.p-value: 0.7695Log Rank
Secondary
Change From Baseline in Pain and Symptom Burden Assessment on the Modified Brief Pain Inventory-Short Form (mBPI-sf)
The mBPI-sf is an 11-item instrument used as a multiple-item measure of cancer pain intensity. In addition to pain intensity (4 items), the mBPI-sf is designed for participants to record the presence of pain in general, pain relief, and pain interference with function (general activity, mood, ability to walk, ability to perform normal work, relations with others, sleep, enjoyment of life). Responses for the mBPI-sf items are captured through the use of 11-point numeric rating scales anchored at 0 (no pain or does not interfere) and 10 (pain as bad as you can imagine or completely interferes). The mBPI-sf recall period is 24 hours and typical completion time for this instrument is less than 5 minutes. Mean Interference Score data is reported here. Least square (LS) Mean value was controlled for Treatment, visit, Treatment\*Visit and baseline.
Time frame: Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months)
Population: All enrolled participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Pain and Symptom Burden Assessment on the Modified Brief Pain Inventory-Short Form (mBPI-sf) | 0 units on a scale | Standard Error 0.18 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Pain and Symptom Burden Assessment on the Modified Brief Pain Inventory-Short Form (mBPI-sf) | 0.20 units on a scale | Standard Error 0.18 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Pain and Symptom Burden Assessment on the Modified Brief Pain Inventory-Short Form (mBPI-sf) | 0.31 units on a scale | Standard Error 0.19 |
p-value: 0.232MMRM Model
Secondary
Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)
EORTC QLQ-C30 v3.0 was a self-administered questionnaire with multidimensional scales that measures 5 functional domains (physical, role, cognitive, emotional, and social), global health status, and symptom scales of fatigue, pain, nausea and vomiting, dyspnea, loss of appetite, insomnia, constipation and diarrhea, and financial difficulties. A linear transformation is applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For functional domains and global health status, higher scores represent a better level of functioning. For symptoms scales, higher scores represented a greater degree of symptoms. LS Mean value was controlled for Treatment, visit, Treatment\*Visit and baseline.
Time frame: Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months)
Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline EORTC QLQ-C30 data for each EORTC QLQ-C30 items.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Emotional functioning | 2.4 units on a scale | Standard Error 1.7 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Diarrhoea | 21.5 units on a scale | Standard Error 2.2 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Fatigue | 1.8 units on a scale | Standard Error 1.9 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Role functioning | -2.7 units on a scale | Standard Error 2.2 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Financial difficulties | 0.8 units on a scale | Standard Error 2 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Insomnia | -4.4 units on a scale | Standard Error 2.1 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Physical functioning | -1.0 units on a scale | Standard Error 1.6 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Global health status | -2.9 units on a scale | Standard Error 1.6 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Nausea and vomiting | 6.3 units on a scale | Standard Error 1.4 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Social functioning | -0.9 units on a scale | Standard Error 1.9 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Appetite loss | 6.3 units on a scale | Standard Error 2.3 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Dyspnoea | 0.7 units on a scale | Standard Error 1.9 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Cognitive functioning | -1.8 units on a scale | Standard Error 1.4 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Constipation | -6.3 units on a scale | Standard Error 1.9 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Pain | -2.5 units on a scale | Standard Error 2.1 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Nausea and vomiting | 5.6 units on a scale | Standard Error 1.4 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Pain | 3.1 units on a scale | Standard Error 2.1 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Dyspnoea | 2.9 units on a scale | Standard Error 2 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Insomnia | -1.6 units on a scale | Standard Error 2.2 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Appetite loss | 5.5 units on a scale | Standard Error 2.4 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Constipation | -10.5 units on a scale | Standard Error 1.9 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Diarrhoea | 25.3 units on a scale | Standard Error 2.3 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Financial difficulties | -1.9 units on a scale | Standard Error 2.1 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Global health status | -5.9 units on a scale | Standard Error 1.7 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Physical functioning | -4.4 units on a scale | Standard Error 1.6 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Role functioning | -5.0 units on a scale | Standard Error 2.3 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Emotional functioning | -0.4 units on a scale | Standard Error 1.8 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Cognitive functioning | -1.1 units on a scale | Standard Error 1.5 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Social functioning | -0.9 units on a scale | Standard Error 1.9 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Fatigue | 7.0 units on a scale | Standard Error 2 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Role functioning | -8.2 units on a scale | Standard Error 2.4 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Constipation | -3.4 units on a scale | Standard Error 2 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Nausea and vomiting | 2.2 units on a scale | Standard Error 1.5 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Emotional functioning | 1.1 units on a scale | Standard Error 1.8 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Appetite loss | 2.4 units on a scale | Standard Error 2.5 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Fatigue | 4.7 units on a scale | Standard Error 2.1 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Cognitive functioning | -1.6 units on a scale | Standard Error 1.6 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Insomnia | 2.0 units on a scale | Standard Error 2.3 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Pain | 4.3 units on a scale | Standard Error 2.2 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Global health status | -1.9 units on a scale | Standard Error 1.8 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Financial difficulties | -3.2 units on a scale | Standard Error 2.2 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Social functioning | -2.4 units on a scale | Standard Error 2 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Functional scale: Physical functioning | -4.5 units on a scale | Standard Error 1.7 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Diarrhoea | 2.2 units on a scale | Standard Error 2.4 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | Symptom scale: Dyspnoea | 3.7 units on a scale | Standard Error 2.1 |
Comparison: Global health statusp-value: 0.689MMRM Model
Comparison: Functional scales: Physical functioningp-value: 0.141MMRM Model
Comparison: Functional scale: Role functioningp-value: 0.095MMRM Model
Comparison: Functional scale: Emotional functioningp-value: 0.591MMRM Model
Comparison: Functional scale: Cognitive functioningp-value: 0.935MMRM Model
Comparison: Functional scale: Social functioningp-value: 0.578MMRM Model
Comparison: Symptom scale: Fatiguep-value: 0.308MMRM Model
Comparison: Symptom scale: Nausea and vomitingp-value: 0.043MMRM Model
Comparison: Symptom scale: Painp-value: 0.026MMRM Model
Comparison: Symptom scale: Dyspnoeap-value: 0.276MMRM Model
Comparison: Symptom scale: Insomniap-value: 0.041MMRM Model
Comparison: Symptom scale: Appetite lossp-value: 0.262MMRM Model
Comparison: Symptom scale: Constipationp-value: 0.285MMRM Model
Comparison: Symptom scale: Diarrhoeap-value: <0.001MMRM Model
Comparison: Symptom scale: Financial difficultiesp-value: 0.18MMRM Model
Secondary
Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score
The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status. Participants completed the 5-level (no problem, slight problem, moderate problem, severe problem, and inability or extreme problem), 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire concerning their current health state. Five dimensions of health status are each assessed with 5 response options and scored as a composite index which were anchored on a scale of 0 to 1 with a higher score representing better health status.LS Mean value was controlled for Treatment, visit, Treatment\*Visit and baseline.
Time frame: Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months)
Population: All enrolled participants who received at least one dose of study drug with baseline and post-baseline EQ-5D 5L data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score | 0.01 units on a scale | Standard Error 0.02 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score | -0.01 units on a scale | Standard Error 0.02 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score | -0.04 units on a scale | Standard Error 0.02 |
p-value: 0.033MMRM Model
p-value: 0.275MMRM Model
Secondary
Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS)
European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) is a standardized measure of health status of the participant. The EQ-5D-5L is assessed using a visual analog scale (VAS) that ranged from 0 to 100 millimeter (mm), where 0 is the worst health you can imagine and 100 is the best health you can imagine. A higher score indicates better health state. LS Mean value was controlled for Treatment, visit, Treatment\*Visit and baseline.
Time frame: Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months)
Population: All enrolled participants who received at least one dose of study drug with baseline and post-baseline EQ-5D 5L VAS data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) | 0.61 millimeter (mm) | Standard Error 1.4 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) | -1.64 millimeter (mm) | Standard Error 1.4 |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) | -0.61 millimeter (mm) | Standard Error 1.5 |
p-value: 0.546MMRM Model
p-value: 0.62MMRM Model
Secondary
Duration of Response (DoR)
DoR was the time from the date of first evidence of complete response or partial response to the date of objective progression or the date of death due to any cause, whichever is earlier. CR and PR were defined using the RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. If a responder was not known to have died or have objective progression as of the data inclusion cutoff date, duration of response was censored at the last adequate tumor assessment date.
Time frame: Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (Up To 36 Months)
Population: All enrolled participants who received at least one dose of study drug and achieved CR or PR.Censored participants = 12 in 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant~; 3 participants in 150 mg Abemaciclib + 8 mg/kg Trastuzumab and 11 participants in 8 mg/kg Trastuzumab + Standard of Care Chemotherapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Duration of Response (DoR) | 12.5 Months |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Duration of Response (DoR) | 9.5 Months |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Duration of Response (DoR) | NA Months |
Secondary
Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)
ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions.
Time frame: Baseline to Objective Disease Progression (Up To 36 Months)
Population: All enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) | 32.9 Percentage of participants |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) | 13.9 Percentage of participants |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) | 13.9 Percentage of participants |
Secondary
Percentage of Participants With 1 Year Overall Survival (OS)
OS is defined as the time from the date of randomization until death from any cause. For participants not known to have died by the data-inclusion cutoff date, OS is censored at the last date they were known to be alive. For each treatment arm OS rate at 1 year from the date of randomization was determined using the OS times and was estimated using the Kaplan-Meier method.
Time frame: Randomization to date of death from any cause assessed at 1 year
Population: All randomized participants (including the censored participants). Number of participants censored were 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant = 62, 150 mg Abemaciclib + 8 mg/kg Trastuzumab = 62, and 8 mg/kg Trastuzumab + Standard of Care Chemotherapy = 58.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Percentage of Participants With 1 Year Overall Survival (OS) | 77.2 percentage of participants |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Percentage of Participants With 1 Year Overall Survival (OS) | 77.4 percentage of participants |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Percentage of Participants With 1 Year Overall Survival (OS) | 69.8 percentage of participants |
p-value: 0.24195% CI: [0.36, 1.3]Log Rank
p-value: 0.31395% CI: [0.38, 1.36]Log Rank
Secondary
Percentage of Participants With 2 Year OS
OS is defined as the time from the date of randomization until death from any cause. For participants not known to have died by the data-inclusion cutoff date, OS is censored at the last date they were known to be alive. For each treatment arm OS rate at 2 years from the date of randomization was determined using the OS times and was estimated using the Kaplan-Meier method.
Time frame: Randomization to date of death from any cause assessed at 2 years
Population: All randomized participants (including the censored participants). Number of participants censored were 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant = 47, 150 mg Abemaciclib + 8 mg/kg Trastuzumab = 47, and 8 mg/kg Trastuzumab + Standard of Care Chemotherapy = 41.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Percentage of Participants With 2 Year OS | 55.8 percentage of participants |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Percentage of Participants With 2 Year OS | 55.7 percentage of participants |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Percentage of Participants With 2 Year OS | 43.0 percentage of participants |
p-value: 0.10495% CI: [0.42, 1.08]Log Rank
p-value: 0.1295% CI: [0.43, 1.1]Log Rank
Secondary
Percentage of Participants With 3 Year OS
OS is defined as the time from the date of randomization until death from any cause. For participants not known to have died by the data-inclusion cutoff date, OS is censored at the last date they were known to be alive. For each treatment arm OS rate at 3 years from the date of randomization was determined using the OS times and was estimated using the Kaplan-Meier method.
Time frame: Randomization to date of death from any cause assessed at 3 years
Population: All randomized participants (including the censored participants). Number of participants censored were 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant = 41, 150 mg Abemaciclib + 8 mg/kg Trastuzumab = 37, and 8 mg/kg Trastuzumab + Standard of Care Chemotherapy = 33.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Percentage of Participants With 3 Year OS | 46.7 percentage of participants |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Percentage of Participants With 3 Year OS | 40.2 percentage of participants |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Percentage of Participants With 3 Year OS | 29.9 percentage of participants |
p-value: 0.04995% CI: [0.42, 1]Log Rank
p-value: 0.15395% CI: [0.48, 1.12]Log Rank
Secondary
Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR)
Disease Control Rate (DCR) was the percentage of participants with a best overall response of CR, PR, or Stable Disease (SD) as per Response using RECIST v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions.
Time frame: Baseline to Objective Disease Progression (Up To 36 Months)
Population: All enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) | 78.5 Percentage of participants |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) | 74.7 Percentage of participants |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) | 67.1 Percentage of participants |
Secondary
Percentage of Participants With Best Overall Response of CR, PR, or SD With Duration of SD for at Least 6 Months: Clinical Benefit Rate (CBR)
Clinical benefit rate defined as percentage of participants with best overall response of CR, PR, or SD with a duration of at least 6 months. CR, PR, or SD were defined using RECIST, v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. Percentage of participants = (participants with CR+PR+SD with a duration of at least 6 months /number of participants enrolled) \*100.
Time frame: Date of CR, PR or SD to 6 Months Post CR, PR or SD (Up To 36 Months)
Population: All enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Percentage of Participants With Best Overall Response of CR, PR, or SD With Duration of SD for at Least 6 Months: Clinical Benefit Rate (CBR) | 58.2 Percentage of participants |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Percentage of Participants With Best Overall Response of CR, PR, or SD With Duration of SD for at Least 6 Months: Clinical Benefit Rate (CBR) | 45.6 Percentage of participants |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | Percentage of Participants With Best Overall Response of CR, PR, or SD With Duration of SD for at Least 6 Months: Clinical Benefit Rate (CBR) | 38.0 Percentage of participants |
Secondary
Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20)
Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20) was evaluated. M2 and M20 are 2 major active metabolites of abemaciclib.
Time frame: Cycle(C)1 Day(D)1,C1D15, C2D1, C2D8, C3D1,C3D15, C4D1, C5D1:pre-dose; C1D1, C2D1, C3D1, C4D1, C5D1:post-dose
Population: All enrolled participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20) | Abemaciclib | 134 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 77 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20) | M2 | 72.0 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 120 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20) | M20 | 136 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 120 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20) | Abemaciclib | 155 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 53 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20) | M2 | 96.5 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 120 |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20) | M20 | 181 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 130 |