Breast Cancer
Conditions
Keywords
MONARCH 3
Brief summary
The main purpose of this study is to evaluate how effective nonsteroidal aromatase inhibitors (NSAI) plus abemaciclib are in postmenopausal women with breast cancer. Participants will be randomized to abemaciclib or placebo in a 2:1 ratio.
Interventions
DRUGAnastrozole
Administered orally
DRUGLetrozole
Administered orally
DRUGPlacebo
Administered orally
DRUGAbemaciclib
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a diagnosis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer * Have locoregionally recurrent disease not amenable to resection or radiation therapy with curative intent or metastatic disease * Have postmenopausal status * Have either measurable disease or nonmeasurable bone-only disease * Have a performance status ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale * Have adequate organ function * Have discontinued previous localized radiotherapy for palliative purposes or for lytic lesions at risk of fracture prior to randomization and recovered from the acute effects of therapy * Are able to swallow capsules
Exclusion criteria
* Have visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis * Have inflammatory breast cancer * Have clinical evidence or a history of central nervous system (CNS) metastasis * Are currently receiving or have previously received endocrine therapy for locoregionally recurrent or metastatic breast cancer * Have received prior (neo)adjuvant endocrine therapy with a disease-free interval ≤12 months from completion of treatment * Are currently receiving or have previously received chemotherapy for locoregionally recurrent or metastatic breast cancer * Have received prior treatment with everolimus * Have received prior treatment with any cyclin-dependent kinase (CDK) 4/6 inhibitor (or participated in any CDK4/6 inhibitor clinical trial for which treatment assignment is still blinded) * Have initiated bisphosphonates or approved receptor activator of nuclear factor kappa-B ligand (RANK-L) targeted agents \<7 days prior to randomization * Are currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged not to be scientifically or medically compatible with this study * Have 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 had major surgery within 14 days prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Randomization to Progressive Disease or Death Due to Any Cause (Up to 32 Months) | PFS defined as the time from the first day of therapy to the first evidence of disease progression as defined by RECIST v1.1 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 randomization, 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 |
|---|---|---|
| Overall Survival (OS) | Randomization to Progressive Disease or Death Due to Any Cause (Estimated Up to 82 Months) | OS defined as the time from first dose date to the date of death due to any cause. For each participant who is not known to have died as of the data-inclusion cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive. |
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) | Randomization to Progressive Disease or Death Due to Any Cause (Up to 32 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) | CR or PR to Disease Progression or Death Due to Any Cause (Up to 32 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 CR, PR or Stable Disease (SD) (Disease Control Rate [DCR]) | Randomization to Progressive Disease or Death Due to Any Cause (Up to 32 Months) | DCR was the percentage of participants with a best overall response of CR, PR, or 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 Tumor Response of SD for at Least 6 Months, PR, or CR (Clinical Benefit Rate [CBR]) | Randomization to Progressive Disease or Death Due to Any Cause (Up to 32 Months) | CBR 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. |
| Change From Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Functional Scale Scores | Baseline, End of Study (Up to 32 Months) | EORTC QLQ-C30 v3.0 is 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.Functional scale options are defined on a 7-point scale ranging from 1, "Very poor" to 7, "Excellent". A linear transformation is applied to standardize the raw scores to range between 0 and 100 with higher score indicating better functioning. For functional domains and global health status, higher scores represent a better level of functioning. Least Square(LS) Mean was calculated using Mixed Model Repeated Measures (MMRM) model with treatment, Visit, Treatment\*Visit and Baseline. |
| Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Baseline, End of Study (Up to 32 Months) | EORTC QLQ-C30 v3.0 is 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. Symptom scale ranges from: 1, "Not at all"; 2, "A little"; 3, "Quite a bit"; to 4, "Very much." A linear transformation is applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For symptoms scales, higher scores indicated greater symptom burden. Least Square(LS) Mean was calculated using Mixed Model Repeated Measures (MMRM) model with treatment, Visit, Treatment\*Visit and Baseline. Small changes are generally defined as at least a 3, 4 or 5 point change from baseline. |
| Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire | Baseline, End of Study (Up to 32 Months) | The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with responses from: 1, "Not at all"; 2, "A little"; 3, "Quite a bit"; to 4, "Very much". All scores are converted to a 0 to 100 scale. A higher score representing a higher ("better") level of functioning (BR23: body image, sexual functioning, future perspective), or a higher ("worse") level of symptoms. Least Square (LS) Mean was calculated using Mixed Model Repeated Measures (MMRM) model with treatment, Visit, Treatment\*Visit and Baseline. |
| Change From Baseline to End of Study in Health Status on the EuroQuol 5-Dimension 5 Level (EuroQol-5D 5L) Index Value | Baseline, End of Study (Up to 32 Months) | The EuroQol-5D (version 5L) is a brief self-administered, validated instrument consisting of 2 parts.The first part consists of 5 descriptors of current health state (mobility, self care, usual activities, pain/discomfort, and anxiety/ depression); a participant is asked to rate each state on a five level scale (no problem, slight problem, moderate problem, severe problem and extreme problem) with higher levels indicating greater severity/ impairment. Published weights are available that allow for the creation of a single summary score called the EQ-5D index that ranges from 0 to 1, with low scores representing a higher level of dysfunction and 1 as perfect health. Minimally important differences in the EQ-5D index score are 0.06 or greater in cancer patients. Least Square(LS) Mean was calculated using Mixed Model Repeated Measures (MMRM) model with treatment, Visit, Treatment\*Visit and Baseline. |
| Change From Baseline to End of Study in Health Status on the EuroQol-5D 5L Visual Analog Scale (VAS) Scores Scale | Baseline, End of Study (Up to 32 Months) | The EuroQol-5D (version 5L) is a brief self-administered, validated instrument consisting of 2 parts. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state). Minimally important differences in the EQ-5D VAS score are 7 or greater in cancer patients. Least Square(LS) Mean was calculated using Mixed Model Repeated Measures (MMRM) model with treatment, Visit, Treatment\*Visit and Baseline. |
| Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity [AUC(0-∞)] of Abemaciclib and Its Metabolites M2 and M20 | Cycle 1 Day 1; 2 to 4 hours (h) post dose, Cycle 2 Day 1; 3 h post dose; 7 h post dose, Cycle 3 Day 1; pre dose, 3 h post dose | Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity \[AUC(0-∞)\] of Abemaciclib and Its Metabolites M2 and M20 |
| PK: Hepatic Clearance of Abemaciclib, and Apparent Hepatic Clearance of Its Metabolites M2 and M20 | Cycle 1 Day 1; 2 to 4 hours (h) post dose, Cycle 2 Day 1; 3 h post dose; 7 h post dose, Cycle 3 Day 1; pre dose, 3 h post dose | PK: Hepatic Clearance of Abemaciclib, and apparent hepatic clearance of its Metabolites M2 and M20 |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Greece, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Russia, Slovakia, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORCall 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
Eli Lilly and Company
Participant flow
Pre-assignment details
Completers are participants who died.
Participants by arm
| Arm | Count |
|---|---|
| Abemaciclib + NSAI 150 milligrams (mg) Abemaciclib orally every 12 hours plus either 1 mg anastrozole or 2.5 mg letrozole orally once daily for 28 days (28 day cycles). | 328 |
| Placebo + NSAI Placebo orally every 12 hours plus either 1 mg anastrozole or 2.5 mg letrozole orally once daily for 28 days (28 day cycles). | 165 |
| Total | 493 |
Baseline characteristics
| Characteristic | Placebo + NSAI | Abemaciclib + NSAI | Total |
|---|---|---|---|
| Age, Continuous | 62.92 years STANDARD_DEVIATION 9.96 | 63.13 years STANDARD_DEVIATION 9.92 | 63.05 years STANDARD_DEVIATION 9.92 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 32 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 125 Participants | 230 Participants | 355 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 28 Participants | 66 Participants | 94 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) Asian | 45 Participants | 103 Participants | 148 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 5 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 28 Participants | 39 Participants |
| Race (NIH/OMB) White | 102 Participants | 186 Participants | 288 Participants |
| Region of Enrollment Australia | 6 Participants | 9 Participants | 15 Participants |
| Region of Enrollment Austria | 3 Participants | 10 Participants | 13 Participants |
| Region of Enrollment Belgium | 7 Participants | 14 Participants | 21 Participants |
| Region of Enrollment Canada | 11 Participants | 14 Participants | 25 Participants |
| Region of Enrollment France | 11 Participants | 30 Participants | 41 Participants |
| Region of Enrollment Germany | 5 Participants | 11 Participants | 16 Participants |
| Region of Enrollment Greece | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Israel | 19 Participants | 28 Participants | 47 Participants |
| Region of Enrollment Italy | 11 Participants | 11 Participants | 22 Participants |
| Region of Enrollment Japan | 15 Participants | 38 Participants | 53 Participants |
| Region of Enrollment Mexico | 7 Participants | 22 Participants | 29 Participants |
| Region of Enrollment Netherlands | 4 Participants | 2 Participants | 6 Participants |
| Region of Enrollment New Zealand | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Russia | 6 Participants | 13 Participants | 19 Participants |
| Region of Enrollment Slovakia | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment South Korea | 18 Participants | 41 Participants | 59 Participants |
| Region of Enrollment Spain | 14 Participants | 16 Participants | 30 Participants |
| Region of Enrollment Sweden | 1 Participants | 3 Participants | 4 Participants |
| Region of Enrollment Taiwan | 9 Participants | 23 Participants | 32 Participants |
| Region of Enrollment Turkey | 3 Participants | 9 Participants | 12 Participants |
| Region of Enrollment United Kingdom | 2 Participants | 7 Participants | 9 Participants |
| Region of Enrollment United States | 12 Participants | 24 Participants | 36 Participants |
| Sex: Female, Male Female | 165 Participants | 328 Participants | 493 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 63 / 328 | 30 / 165 |
| other Total, other adverse events | 322 / 327 | 141 / 161 |
| serious Total, serious adverse events | 102 / 327 | 27 / 161 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS defined as the time from the first day of therapy to the first evidence of disease progression as defined by RECIST v1.1 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 randomization, 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: Randomization to Progressive Disease or Death Due to Any Cause (Up to 32 Months)
Population: All randomized participants who had evaluable data. Censored participants: Abemaciclib + NSAI = 190 and Placebo + NSAI =57.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abemaciclib + NSAI | Progression Free Survival (PFS) | 28.18 Months |
| Placebo + NSAI | Progression Free Survival (PFS) | 14.76 Months |
p-value: 0.00000295% CI: [0.418, 0.698]Log Rank
Secondary
Change From Baseline to End of Study in Health Status on the EuroQol-5D 5L Visual Analog Scale (VAS) Scores Scale
The EuroQol-5D (version 5L) is a brief self-administered, validated instrument consisting of 2 parts. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state). Minimally important differences in the EQ-5D VAS score are 7 or greater in cancer patients. Least Square(LS) Mean was calculated using Mixed Model Repeated Measures (MMRM) model with treatment, Visit, Treatment\*Visit and Baseline.
Time frame: Baseline, End of Study (Up to 32 Months)
Population: All randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Abemaciclib + NSAI | Change From Baseline to End of Study in Health Status on the EuroQol-5D 5L Visual Analog Scale (VAS) Scores Scale | 0.49 millimeter (mm) | Standard Error 0.78 |
| Placebo + NSAI | Change From Baseline to End of Study in Health Status on the EuroQol-5D 5L Visual Analog Scale (VAS) Scores Scale | 1.51 millimeter (mm) | Standard Error 1.15 |
p-value: 0.466Mixed Models Analysis
Secondary
Change From Baseline to End of Study in Health Status on the EuroQuol 5-Dimension 5 Level (EuroQol-5D 5L) Index Value
The EuroQol-5D (version 5L) is a brief self-administered, validated instrument consisting of 2 parts.The first part consists of 5 descriptors of current health state (mobility, self care, usual activities, pain/discomfort, and anxiety/ depression); a participant is asked to rate each state on a five level scale (no problem, slight problem, moderate problem, severe problem and extreme problem) with higher levels indicating greater severity/ impairment. Published weights are available that allow for the creation of a single summary score called the EQ-5D index that ranges from 0 to 1, with low scores representing a higher level of dysfunction and 1 as perfect health. Minimally important differences in the EQ-5D index score are 0.06 or greater in cancer patients. Least Square(LS) Mean was calculated using Mixed Model Repeated Measures (MMRM) model with treatment, Visit, Treatment\*Visit and Baseline.
Time frame: Baseline, End of Study (Up to 32 Months)
Population: All randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Abemaciclib + NSAI | Change From Baseline to End of Study in Health Status on the EuroQuol 5-Dimension 5 Level (EuroQol-5D 5L) Index Value | 0.01 units on a scale | Standard Error 0.01 |
| Placebo + NSAI | Change From Baseline to End of Study in Health Status on the EuroQuol 5-Dimension 5 Level (EuroQol-5D 5L) Index Value | 0.01 units on a scale | Standard Error 0.01 |
p-value: 0.688Mixed Models Analysis
Secondary
Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire
The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with responses from: 1, Not at all; 2, A little; 3, Quite a bit; to 4, Very much. All scores are converted to a 0 to 100 scale. A higher score representing a higher (better) level of functioning (BR23: body image, sexual functioning, future perspective), or a higher (worse) level of symptoms. Least Square (LS) Mean was calculated using Mixed Model Repeated Measures (MMRM) model with treatment, Visit, Treatment\*Visit and Baseline.
Time frame: Baseline, End of Study (Up to 32 Months)
Population: All randomized participants.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire | Body image | -4.5 score on a scale | Standard Error 1.1 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire | Sexual functioning | -0.2 score on a scale | Standard Error 0.7 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire | Future perspective | 12.7 score on a scale | Standard Error 1.3 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire | Systemic therapy side effects | 8.15 score on a scale | Standard Error 0.68 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire | Breast symptoms | -6.12 score on a scale | Standard Error 0.64 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire | Arm symptoms | -1.14 score on a scale | Standard Error 0.87 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire | Breast symptoms | -6.23 score on a scale | Standard Error 0.93 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire | Body image | 0.6 score on a scale | Standard Error 1.6 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire | Systemic therapy side effects | 3.68 score on a scale | Standard Error 0.98 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire | Sexual functioning | -0.1 score on a scale | Standard Error 1 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire | Arm symptoms | -2.23 score on a scale | Standard Error 1.27 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-Breast23 Questionnaire | Future perspective | 11.9 score on a scale | Standard Error 1.9 |
Secondary
Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores
EORTC QLQ-C30 v3.0 is 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. Symptom scale ranges from: 1, Not at all; 2, A little; 3, Quite a bit; to 4, Very much. A linear transformation is applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For symptoms scales, higher scores indicated greater symptom burden. Least Square(LS) Mean was calculated using Mixed Model Repeated Measures (MMRM) model with treatment, Visit, Treatment\*Visit and Baseline. Small changes are generally defined as at least a 3, 4 or 5 point change from baseline.
Time frame: Baseline, End of Study (Up to 32 Months)
Population: All randomized participants.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Nausea and Vomiting | 2.4 score on a scale | Standard Error 0.6 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Appetite loss | 0.2 score on a scale | Standard Error 1.1 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Dyspnea | 0.9 score on a scale | Standard Error 1 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Constipation | -0.8 score on a scale | Standard Error 0.9 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Pain | -4.8 score on a scale | Standard Error 1 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Diarrhea | 18.2 score on a scale | Standard Error 1 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Insomnia | -1.7 score on a scale | Standard Error 1.2 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Financial difficulties | -0.7 score on a scale | Standard Error 1.1 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Fatigue | 2.4 score on a scale | Standard Error 1 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Financial difficulties | -1.2 score on a scale | Standard Error 1.6 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Fatigue | -2.6 score on a scale | Standard Error 1.4 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Nausea and Vomiting | -0.4 score on a scale | Standard Error 0.9 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Pain | -5.7 score on a scale | Standard Error 1.5 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Dyspnea | -1.6 score on a scale | Standard Error 1.4 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Insomnia | -4.1 score on a scale | Standard Error 1.7 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Appetite loss | -3.9 score on a scale | Standard Error 1.6 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Constipation | 1.6 score on a scale | Standard Error 1.3 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the EORTC QLQ-C30 Symptom Scale Scores | Diarrhea | -0.5 score on a scale | Standard Error 1.5 |
Secondary
Change From Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Functional Scale Scores
EORTC QLQ-C30 v3.0 is 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.Functional scale options are defined on a 7-point scale ranging from 1, Very poor to 7, Excellent. A linear transformation is applied to standardize the raw scores to range between 0 and 100 with higher score indicating better functioning. For functional domains and global health status, higher scores represent a better level of functioning. Least Square(LS) Mean was calculated using Mixed Model Repeated Measures (MMRM) model with treatment, Visit, Treatment\*Visit and Baseline.
Time frame: Baseline, End of Study (Up to 32 Months)
Population: All randomized participants.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Functional Scale Scores | Role | -1.4 score on a scale | Standard Error 1.1 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Functional Scale Scores | Cognitive | -4.0 score on a scale | Standard Error 0.9 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Functional Scale Scores | Emotional | 4.7 score on a scale | Standard Error 0.9 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Functional Scale Scores | Social | -0.1 score on a scale | Standard Error 1 |
| Abemaciclib + NSAI | Change From Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Functional Scale Scores | Physical | -1.0 score on a scale | Standard Error 0.9 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Functional Scale Scores | Social | 3.3 score on a scale | Standard Error 1.4 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Functional Scale Scores | Physical | 1.7 score on a scale | Standard Error 1.2 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Functional Scale Scores | Role | 2.9 score on a scale | Standard Error 1.6 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Functional Scale Scores | Emotional | 4.0 score on a scale | Standard Error 1.3 |
| Placebo + NSAI | Change From Baseline to End of Study in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Functional Scale Scores | Cognitive | -4.0 score on a scale | Standard Error 1.3 |
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: CR or PR to Disease Progression or Death Due to Any Cause (Up to 32 Months)
Population: All randomized participants who had evaluable data. Censored participants: Abemaciclib + NSAI = 112 and Placebo + NSAI =28.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abemaciclib + NSAI | Duration of Response (DoR) | 27.39 Months |
| Placebo + NSAI | Duration of Response (DoR) | 17.46 Months |
Secondary
Overall Survival (OS)
OS defined as the time from first dose date to the date of death due to any cause. For each participant who is not known to have died as of the data-inclusion cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive.
Time frame: Randomization to Progressive Disease or Death Due to Any Cause (Estimated Up to 82 Months)
Secondary
Percentage of Participants With 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: Randomization to Progressive Disease or Death Due to Any Cause (Up to 32 Months)
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Abemaciclib + NSAI | Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) | 49.7 Percentage of Participants |
| Placebo + NSAI | Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) | 37 Percentage of Participants |
p-value: 0.005Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With CR, PR or Stable Disease (SD) (Disease Control Rate [DCR])
DCR was the percentage of participants with a best overall response of CR, PR, or 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: Randomization to Progressive Disease or Death Due to Any Cause (Up to 32 Months)
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Abemaciclib + NSAI | Percentage of Participants With CR, PR or Stable Disease (SD) (Disease Control Rate [DCR]) | 88.7 Percentage of Participants |
| Placebo + NSAI | Percentage of Participants With CR, PR or Stable Disease (SD) (Disease Control Rate [DCR]) | 86.7 Percentage of Participants |
p-value: 0.501Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Tumor Response of SD for at Least 6 Months, PR, or CR (Clinical Benefit Rate [CBR])
CBR 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: Randomization to Progressive Disease or Death Due to Any Cause (Up to 32 Months)
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Abemaciclib + NSAI | Percentage of Participants With Tumor Response of SD for at Least 6 Months, PR, or CR (Clinical Benefit Rate [CBR]) | 78.0 Percentage of Participants |
| Placebo + NSAI | Percentage of Participants With Tumor Response of SD for at Least 6 Months, PR, or CR (Clinical Benefit Rate [CBR]) | 71.5 Percentage of Participants |
p-value: 0.101Cochran-Mantel-Haenszel
Secondary
Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity [AUC(0-∞)] of Abemaciclib and Its Metabolites M2 and M20
Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity \[AUC(0-∞)\] of Abemaciclib and Its Metabolites M2 and M20
Time frame: Cycle 1 Day 1; 2 to 4 hours (h) post dose, Cycle 2 Day 1; 3 h post dose; 7 h post dose, Cycle 3 Day 1; pre dose, 3 h post dose
Population: All randomized participants who received at least one dose of study drug with evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Abemaciclib + NSAI | Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity [AUC(0-∞)] of Abemaciclib and Its Metabolites M2 and M20 | Abemaciclib | 3360 nanogram*hours/milliliter (ng*h/mL) | Geometric Coefficient of Variation 36.6 |
| Abemaciclib + NSAI | Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity [AUC(0-∞)] of Abemaciclib and Its Metabolites M2 and M20 | M2 | 1290 nanogram*hours/milliliter (ng*h/mL) | Geometric Coefficient of Variation 75.8 |
| Abemaciclib + NSAI | Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity [AUC(0-∞)] of Abemaciclib and Its Metabolites M2 and M20 | M20 | 2300 nanogram*hours/milliliter (ng*h/mL) | Geometric Coefficient of Variation 74.4 |
Secondary
PK: Hepatic Clearance of Abemaciclib, and Apparent Hepatic Clearance of Its Metabolites M2 and M20
PK: Hepatic Clearance of Abemaciclib, and apparent hepatic clearance of its Metabolites M2 and M20
Time frame: Cycle 1 Day 1; 2 to 4 hours (h) post dose, Cycle 2 Day 1; 3 h post dose; 7 h post dose, Cycle 3 Day 1; pre dose, 3 h post dose
Population: All randomized participants who received at least one dose of study drug with evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Abemaciclib + NSAI | PK: Hepatic Clearance of Abemaciclib, and Apparent Hepatic Clearance of Its Metabolites M2 and M20 | M20 | 26.0 liters/hour (L/h) | Geometric Coefficient of Variation 46.4 |
| Abemaciclib + NSAI | PK: Hepatic Clearance of Abemaciclib, and Apparent Hepatic Clearance of Its Metabolites M2 and M20 | Abemaciclib | 23.0 liters/hour (L/h) | Geometric Coefficient of Variation 26.7 |
| Abemaciclib + NSAI | PK: Hepatic Clearance of Abemaciclib, and Apparent Hepatic Clearance of Its Metabolites M2 and M20 | M2 | 21.6 liters/hour (L/h) | Geometric Coefficient of Variation 50.4 |