Breast Cancer Metastatic
Conditions
Brief summary
Primary Objective: To determine whether amcenestrant per overall survival (os) improves progression free survival (PFS) when compared with an endocrine monotherapy of the choice of the physician, in participants with metastatic or locally advanced breast cancer Secondary Objectives: * To compare the overall survival in the 2 treatment arms * To assess the objective response rate in the 2 treatment arms * To evaluate the disease control rate in the 2 treatment arms * To evaluate the clinical benefit rate in the 2 treatment arms * To evaluate the duration of response in the 2 treatment arms * To evaluate the PFS according to the estrogen receptor 1 gene (ESR1) mutation status in the 2 treatment arms * To evaluate the pharmacokinetics of amcenestrant as single agent * To evaluate health-related quality of life in the 2 treatment arms * To compare the overall safety profile in the 2 treatment arms
Detailed description
The duration of the study for an individual participant will include a period to assess eligibility (screening period) of up to 4 weeks (28 days), a treatment period of at least 1 cycle (28 days of study treatment), and an end of treatment (EOT) visit at least 30 days (or until the participant receive another anticancer therapy, whichever is earlier) following the last administration of study treatment. Study treatment may continue until precluded by unacceptable toxicity, disease progression, death or upon participant's request to stop treatment, or Investigator decision, whichever occurs first. An extension of recruitment for Chinese participants is planned in this study: After completion of randomization in the global part of the study, randomization will continue in China until approximately 90 Chinese participants are randomized.
Interventions
DRUGAmcenestrant
Pharmaceutical form: Capsule Route of administration: Oral
DRUGFulvestrant
Pharmaceutical form: Solution for injection Route of administration: Intramuscular
DRUGAnastrozole
Pharmaceutical form:Tablets or capsules Route of administration: Oral
DRUGLetrozole
Pharmaceutical form: Tablets or capsules Route of administration: Oral
DRUGExemestane
Pharmaceutical form: Tablets or capsules Route of administration: Oral
DRUGTamoxifen
Pharmaceutical form: Tablets or capsules Route of administration: Oral
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: * 18 years or older. * Histological or cytological diagnosis of adenocarcinoma of the breast. * Locally advanced not amenable to radiation therapy or surgery in a curative intent, and/or metastatic disease. * Estrogen receptor(ER) positive status. * Human epidermal growth factor receptor 2 negative status. * Participants must have received no more than 1 prior chemotherapeutic or 1 targeted therapy regimen for advanced/metastatic disease. * In the main study, a prior treatment with a Cyclin-dependent kinase 4 and 6(CDK 4/6) inhibitor is mandatory if this treatment is approved and can be reimbursed for this participant. The percentage of participants without previous CDK 4/6 inhibitor will be capped to 20%. In the Chinese extension cohort, previous treatment with a CDK 4/6 inhibitor will not be mandatory, and there will be no limitation to the number of participants naïve to CDK4/6 inhibitor. * Participants must present a secondary endocrine resistance to endocrine therapy defined as: progression while on endocrine therapy after at least 6 months of treatment for advanced breast cancer, or relapse while on adjuvant endocrine therapy but after the first 2 years, or with a relapse within 12 months after completing adjuvant endocrine therapy. * Male or Female.
Exclusion criteria
* Eastern Cooperative Oncology Group performance status =\>2. * Medical history or ongoing gastrointestinal disorders potentially affecting the absorption of amcenestrant. Participants unable to swallow normally and to take capsules. * Participant with any other cancer. Adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or any other cancer from which the participant has been disease free for greater than 3 years are allowed. * Severe uncontrolled systemic disease at screening . * Participants with known brain metastases that are untreated, symptomatic or require therapy to control symptoms. * Prior treatment with mammalian target of rapamycin inhibitors or any other selective estrogen receptor degrader(SERD) compound, except fulvestrant if stopped for at least 3 months before randomization. * Treatment with drugs that have the potential to inhibit Uridine'5 Diphospho-Glucuronosyl Transferase(UGT) less than 2 weeks before randomization. * Treatment with strong Cytochrome P450 (CYP)3A inducers within 2 weeks before randomization. * Ongoing treatment with drugs that are sensitive substrate of organic anion transporting polypeptide 1B1/B3(OATP1B1/B3) (asunaprevir, atorvastatin, bosentan, danoprevir, fexofenadine, glyburide, nateglinide, pitavastatin, pravastatin, replaglinide, rosuvastatin, and simvastatin acid). * Treatment with anticancer agents (including investigational drugs) less than 3 weeks before randomization. * Inadequate hematological, coagulation, renal and liver functions. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From randomization to the date of first documented tumor progression or death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks) | PFS is defined as the time in months interval from the date of randomization to the date of first documented tumor progression as per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) assessed by independent central review (ICR) or death (due to any cause), whichever comes first. Progressive Disease (PD) as per RECIST 1.1: at least a 20 percent (%) increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method. |
| Chinese Cohort: Progression Free Survival | From randomization to the date of first documented tumor progression or death due to any cause or data cut-off date whichever comes first, up to primary completion date of 15-Feb-2022, a maximum of 121 weeks | PFS is defined as the time in months interval from the date of randomization to the date of first documented tumor progression as per RECIST 1.1 assessed by ICR or death (due to any cause), whichever comes first. PD as per RECIST 1.1: at least a 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization to the death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks) | OS is defined as the time interval from the date of randomization to the date of documented death (due to any cause). In the absence of observation of death, survival time was censored to last date the participant is known to be alive or at the cut-off date, whichever comes first. Analysis was performed by Kaplan-Meier method. |
| Percentage of Participants With Objective Response | From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks) | Objective response is defined as percentage of participants having a partial response (PR) or complete response (CR) according to the RECIST version 1.1 assessed by ICR. As per RECIST 1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Percentage of Participants With Disease Control | From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks) | Disease control is defined as percentage of participants having a confirmed CR, PR, or stable disease (SD) or Non-CR/Non-PD as BOR determined by ICR as per RECIST 1.1 from the date of randomization to the date of end of treatment. As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters. Non-CR/Non-PD: persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. |
| Percentage of Participants With Clinical Benefit | From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks) | Clinical Benefit is defined as percentage of participants having a confirmed CR, PR, SD, or Non-CR/Non-PD for at least 24 weeks determined by ICR as per RECIST 1.1 from the date of randomization to the date of end of treatment. As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. Non-CR/Non-PD: persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. |
| Duration of Response (DOR) | From the date of first response to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks) | DOR is defined as time (in months) from first documented evidence of CR or PR until progressive disease (PD) determined by ICR as per RECIST 1.1 or death from any cause, whichever occurs first. For participants with ongoing response at the time of the analysis, DOR was censored at the date of the last valid disease assessment not showing documented progression performed before the initiation of a new anticancer treatment (if any). As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. |
| Progression Free Survival (PFS) According to Estrogen Receptor 1 Gene (ESR1) Mutation Status | From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks) | PFS defined as the time (in months) interval from the date of randomization to the date of first documented tumor progression as per RECIST 1.1 assessed by ICR or death (due to any cause), whichever comes first. Progression as per RECIST 1.1: at least a 20 percent (%) increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. The mutation status (wild type, mutant) of twelve specific mutations of the ESR1 gene was determined by multiplex droplet digital polymerase chain reaction (ddPCR), including their mutant frequency and concentration. Here, PFS is reported based on the ESR1 mutation status of participants: wild type and mutants. ESR1 was the gene encoding estrogen receptor alpha. ESR1 mutant type breast cancer was a disease where the ESR1 gene had a mutation (i.e., a type of error). ESR1 wild type breast cancer was a disease where the ESR1 gene was normal without a mutation. Analysis was performed by Kaplan-Meier method. |
| Pharmacokinetics: Plasma Concentrations of Amcenestrant | Cycle 1 Day 1: 1.5 hours(h), 4h post-dose, Day 15: pre-dose, Cycle 2 Day 1: pre-dose, 1.5h, 4h, 8h post-dose, Cycle 3 Day 1: pre-dose, Cycle 4 Day 1: pre-dose, Cycle 6 Day 1: pre-dose | Amcenestrant plasma concentrations at specified time points are reported. |
| Within-Participant Steady State Ctrough of Amcenestrant | Predose on Cycle 1 Day 15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 4 Day 1; Cycle 6 Day 1 | Within-participant Steady state Ctrough was defined as the median value of the Ctrough across study using plasma concentration of predose samples at Cycle 1 Day 15 and Day 1 of Cycle 2, 3, 4 and 6 for each individual participant. Average (mean) of all calculated Ctrough values for all participants across study (Cycle 1 Day 15 and Day 1 of Cycle 2, 3, 4 and 6 ) was derived and reported in this outcome measure. |
| Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Baseline, overall treatment duration (Cycle 1 up to Cycle 30 [i.e.,116 weeks]) | EORTC-QLQ-C30: cancer-specific instrument with 30 questions for evaluation of new chemotherapy \& assessment of participant reported outcome. These include 5 functional scales, 9 symptom scales, \& Global Health Status/quality of life scale (GHS/QoL). All 14 items/domains were scored on scale of 1 (not at all) to 4 (very much) and GHS/QoL, scored on scale of 1 (very poor) to 7 (excellent). All scales are transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional \& GHS/QoL = higher level of functioning, \& higher score for symptoms scales = higher symptom burden. Least Square (LS) mean and Standard Error (SE) are derived from MMRM model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values of overall treatment (i.e., each cycle \[Cycle 1 up to Cycle 30\]) was reported in this outcome measure. |
| Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Visual Analog Scale (VAS) Score | Baseline, overall treatment duration (Cycle 1 up to Cycle 30 [i.e.,116 weeks]) | EQ-5D-5L is a standardized measure of health status, provides a simple, generic measure of health for clinical and economic appraisal, and consists of 2 sections: the EQ-5D-5L health state utility index (descriptive system) and the EQ-5D-5L VAS. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. LS mean and SE are derived from MMRM model with change from baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from Baseline values of overall treatment (i.e., each cycle \[Cycle 1 up to Cycle 30\]) was reported in this outcome measure. |
| Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Health Utility Index Value | Baseline, overall treatment duration (Cycle 1 up to Cycle 30 [i.e.,116 weeks]) | EQ-5D-5L: consists of 2 sections: EQ-5D-5L health state utility index (descriptive system) \& VAS. The EQ-5D descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort \& anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, \& extreme problems. Response options are measured with 5-point Likert scale (for 5L version). The EQ-5D-5L responses are converted into single index utility score between 0 to 1, where higher score indicates better health state \& lower score indicate worse health state. LS mean and SE are derived from MMRM model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values overall treatment (i.e., each cycle \[Cycle 1 up to Cycle 30\]) was reported in this outcome measure. |
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Baseline, overall treatment duration (Cycle 1 up to Cycle 30 [i.e.,116 weeks]) | QLQ-BR23: disease-specific Health-related QOL assesses impact of breast cancer \& side effects of treatment. EORTC-QLQ-BR23 contains 23 items: multi-item scales \& single-item measures. 4 functional scales (body image, sexual functioning, sexual enjoyment, future perspective) \& 4 scales related to symptoms of disease or treatment (arm symptoms, breast symptoms, systemic therapy side effects, \& upset by hair loss). All items scored 1 (not at all) to 4 (very much). Scores of all scales transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional scales = better outcome; higher score for symptoms scales = higher symptom burden. LS mean and SE are derived from MMRM model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values of overall treatment (i.e., each cycle \[Cycle 1 up to Cycle 30\]) was reported. |
| Chinese Cohort: Overall Survival | From randomization to the death due to any cause or data cut-off date whichever comes first (maximum duration: 183 weeks) | OS is defined as the time interval from the date of randomization to the date of documented death (due to any cause). In the absence of observation of death, survival time was censored to last date the participant is known to be alive or at the cut-off date, whichever comes first. Analysis was performed by Kaplan-Meier method. |
| Chinese Cohort: Percentage of Participants With Objective Response | From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 183 weeks) | Objective response is defined as percentage of participants having a PR or CR according to the RECIST version 1.1 assessed by ICR. As per RECIST 1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Chinese Cohort: Percentage of Participants With Disease Control | From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 183 weeks) | Disease control is defined as percentage of participants having a confirmed CR, PR, or SD or Non-CR/Non-PD as BOR determined by ICR as per RECIST 1.1 from the date of randomization to the date of end of treatment. As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. Non-CR/Non-PD: persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. |
| Chinese Cohort: Percentage of Participants With Clinical Benefit | From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 183 weeks) | Clinical benefit is defined as percentage of participants having a confirmed CR, PR, SD, or Non-CR/Non-PD for at least 24 weeks determined by ICR as per RECIST 1.1 from the date of randomization to the date of end of treatment. As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. Non-CR/Non-PD: persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. |
| Chinese Cohort: Duration of Response | From the date of first response to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 183 weeks) | DOR is defined as time (in months) from first documented evidence of CR or PR until PD determined by ICR as per RECIST 1.1 or death from any cause, whichever occurs first. For participants with ongoing response at the time of the analysis, DOR was censored at the date of the last valid disease assessment not showing documented progression performed before the initiation of a new anticancer treatment (if any). As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. |
| Chinese Cohort: Progression Free Survival According to Estrogen Receptor 1 Gene Mutation Status | From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 183 weeks) | PFS defined as the time (in months) interval from the date of randomization to the date of first documented tumor progression as per RECIST 1.1 assessed by ICR or death (due to any cause), whichever comes first. Progression as per RECIST 1.1: at least a 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. The mutation status (wild type, mutant) of twelve specific mutations of the ESR1 gene was determined by multiplex ddPCR, including their mutant frequency and concentration. Here, PFS is reported based on the ESR1 mutation status of participants: wild type and mutants. ESR1 was the gene encoding estrogen receptor alpha. ESR1 mutant type breast cancer was a disease where the ESR1 gene had a mutation (i.e., a type of error). ESR1 wild type breast cancer was a disease where the ESR1 gene was normal without a mutation. Analysis was performed by Kaplan-Meier method. |
| Chinese Cohort: Plasma Concentration of Amcenestrant | Cycle 1 Day 1: 1.5 hours(h), 4h post-dose, Cycle 1 Day 15: pre-dose; Cycle 2 Day 1: pre-dose, 1.5h, 4h, 8h post-dose; Cycles 3, 4, and 6 Day 1: pre-dose | Amcenestrant plasma concentrations at specified time points are reported. |
| Chinese Cohort: Within-Participant Steady State Ctrough of Amcenestrant | Pre-dose on Cycle 1 Day 15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 4 Day 1; Cycle 6 Day 1 | Within-participant Steady state Ctrough was defined as the median value of the Ctrough across study using plasma concentration of pre-dose samples at Cycle 1 Day 15 and Day 1 of Cycle 2, 3, 4 and 6 for each individual participant. Average (mean) of all calculated Ctrough values for all participants across study (Cycle 1 Day 15 and Day 1 of Cycle 2, 3, 4 and 6) was derived and reported in this outcome measure. |
| Chinese Cohort: Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Domain Scores | Baseline and up to 183 weeks | EORTC-QLQ-C30: cancer-specific instrument with 30 questions for evaluation of new chemotherapy \& assessment of participant reported outcome. These include 5 functional scales, 9 symptom scales, \& Global Health Status/quality of life scale (GHS/QoL). All 14 items/domains were scored on scale of 1 (not at all) to 4 (very much) and GHS/QoL, scored on scale of 1 (very poor) to 7 (excellent). All scales are transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional \& GHS/QoL = higher level of functioning, \& higher score for symptoms scales = higher symptom burden. LS mean and SE are derived from MMRM model with change from baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values of overall treatment (i.e., 183 weeks) was reported in this outcome measure. |
| Chinese Cohort: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels Score: Visual Analog Scale Score | Baseline and up to 183 weeks | EQ-5D-5L is a standardized measure of health status, provides a simple, generic measure of health for clinical and economic appraisal, and consists of 2 sections: the EQ-5D-5L health state utility index (descriptive system) and the EQ-5D-5L VAS. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. LS mean and SE are derived from MMRM model with change from baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values of overall treatment (i.e., 183 weeks) was reported in this outcome measure. |
| Chinese Cohort: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels Score: Health Utility Index Value | Baseline and up to 183 weeks | EQ-5D-5L: consists of 2 sections: EQ-5D-5L health state utility index (descriptive system) \& VAS. The EQ-5D descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort \& anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, \& extreme problems. Response options are measured with 5-point Likert scale (for 5L version). The EQ-5D-5L responses are converted into single index utility score between 0 to 1, where higher score indicates better health state \& lower score indicate worse health state. LS mean and SE are derived from MMRM model with change from baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values of overall treatment (i.e., 183 weeks) was reported in this outcome measure. |
| Chinese Cohort: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module Domain Scores | Baseline and up to 183 weeks | QLQ-BR23: disease-specific Health-related QOL assesses impact of breast cancer \& side effects of treatment. EORTC-QLQ-BR23 contains 23 items: multi-item scales \& single-item measures. 4 functional scales (body image, sexual functioning, sexual enjoyment, future perspective) \& 4 scales related to symptoms of disease or treatment (arm symptoms, breast symptoms, systemic therapy side effects, \& upset by hair loss). All items scored 1 (not at all) to 4 (very much). Scores of all scales transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional scales = better outcome; higher score for symptoms scales = higher symptom burden. LS mean and SE are derived from MMRM model with change from baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values of overall treatment (i.e., 183 weeks) was reported in this outcome measure. |
| Main Cohort and Chinese Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | From first dose of study treatment (Cycle 1 Day 1) up to 152 weeks for main cohort and 183 weeks for Chinese cohort | An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect or was a medically important event. TEAEs were defined as AEs that developed, worsened (according to the Investigator's opinion), or became serious during the on-treatment period. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, China, Czechia, France, Greece, Israel, Italy, Japan, Latvia, Mexico, Poland, Puerto Rico, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), Ukraine, United States
Contacts
STUDY_DIRECTORClinical Sciences & Operations
Sanofi
Participant flow
Recruitment details
The study was conducted at 88 active centers in 22 countries. 367 participants were screened between 22 October 2019 and 15 April 2021 in main (global) cohort of which 77 were screen failures (mainly due to not meeting eligibility criteria). As pre-specified in the protocol, Chinese participants from main cohort and China cohort were pooled for purpose of analysis of Chinese cohort. 90 participants (including 13 participants from main cohort) were randomized in the Chinese cohort.
Pre-assignment details
Total 367 unique participants enrolled:290 participants(main cohort),77 new participants(Chinese cohort).Randomization was stratified:presence of visceral metastasis(atleast 1 liver/lung metastasis;yes/no),prior treatment with cyclin-dependent kinase 4/6(CDK4/6) inhibitors(yes/no),Eastern Cooperative Oncology Group(ECOG) status(0/1).Study was terminated as it did not meet primary objective of improved progression free survival with amcenestrant versus endocrine treatment of physician's choice.
Participants by arm
| Arm | Count |
|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) Participants received potential control treatment of the choice of the physician depending on each participant's medical condition and in accordance with the approved label. Control treatment included one of the following treatments to be selected before randomization and used as monotherapy: 1) Fulvestrant 500 mg, given as two 5-mL IM injections on Cycle 1 Days 1 and 15, and at Day 1 of each 28-day treatment cycle thereafter; or 2) Aromatase inhibitors (anastrozole 1 mg or letrozole 2.5 mg or exemestane 25 mg), PO, QD; or 3) Tamoxifen 20 mg/day PO, QD or twice a day (maximum exposure: 116 weeks). | 147 |
| Amcenestrant Participants received 4 capsules of 100 mg, amcenestrant PO, QD from Day 1 to Day 28 in each 28-day treatment cycle until precluded by unacceptable toxicity or disease progression or participant's request to stop treatment or Investigator decision, whichever occurred first (maximum exposure: 116 weeks). | 143 |
| Total | 290 |
Baseline characteristics
| Characteristic | Total | — | Physician Choice Endocrine Monotherapy (PCEM) | Amcenestrant |
|---|---|---|---|---|
| Age, Continuous Chinese cohort | 53.1 years STANDARD_DEVIATION 10.7 | 54.2 years STANDARD_DEVIATION 10.7 | — | — |
| Age, Continuous Main cohort | — | 58.7 years STANDARD_DEVIATION 12.2 | 59.2 years STANDARD_DEVIATION 12.5 | 58.2 years STANDARD_DEVIATION 11.8 |
| Race (NIH/OMB) Chinese cohort American Indian or Alaska Native | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Chinese cohort Asian | 42 Participants | 90 Participants | — | — |
| Race (NIH/OMB) Chinese cohort Black or African American | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Chinese cohort More than one race | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Chinese cohort Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Chinese cohort Unknown or Not Reported | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Chinese cohort White | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Main cohort American Indian or Alaska Native | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Main cohort Asian | — | 66 Participants | 34 Participants | 32 Participants |
| Race (NIH/OMB) Main cohort Black or African American | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Main cohort More than one race | — | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Main cohort Native Hawaiian or Other Pacific Islander | — | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Main cohort Unknown or Not Reported | — | 16 Participants | 7 Participants | 9 Participants |
| Race (NIH/OMB) Main cohort White | — | 204 Participants | 102 Participants | 102 Participants |
| Sex: Female, Male Chinese cohort Female | 42 Participants | 89 Participants | — | — |
| Sex: Female, Male Chinese cohort Male | 0 Participants | 1 Participants | — | — |
| Sex: Female, Male Main cohort Female | — | 289 Participants | 146 Participants | 143 Participants |
| Sex: Female, Male Main cohort Male | — | 1 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 52 / 147 | 46 / 143 | 2 / 42 | 6 / 48 |
| other Total, other adverse events | 79 / 147 | 86 / 143 | 14 / 42 | 25 / 48 |
| serious Total, serious adverse events | 16 / 147 | 25 / 143 | 2 / 42 | 5 / 48 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS is defined as the time in months interval from the date of randomization to the date of first documented tumor progression as per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) assessed by independent central review (ICR) or death (due to any cause), whichever comes first. Progressive Disease (PD) as per RECIST 1.1: at least a 20 percent (%) increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method.
Time frame: From randomization to the date of first documented tumor progression or death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
Population: Analysis was performed on the ITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) | Progression Free Survival (PFS) | 3.7 months |
| Amcenestrant | Progression Free Survival (PFS) | 3.6 months |
Comparison: A hierarchical testing procedure was used to ensure a strong control of the overall Type I error. Testing was then performed sequentially in order the outcome measures was reported and continued when previous outcome measure was statistically significant at one-sided 2.5% for the primary and the first secondary outcome.p-value: 0.643795% CI: [0.789, 1.4]Stratified Log-Rank test
Secondary
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores
EORTC-QLQ-C30: cancer-specific instrument with 30 questions for evaluation of new chemotherapy & assessment of participant reported outcome. These include 5 functional scales, 9 symptom scales, & Global Health Status/quality of life scale (GHS/QoL). All 14 items/domains were scored on scale of 1 (not at all) to 4 (very much) and GHS/QoL, scored on scale of 1 (very poor) to 7 (excellent). All scales are transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional & GHS/QoL = higher level of functioning, & higher score for symptoms scales = higher symptom burden. Least Square (LS) mean and Standard Error (SE) are derived from MMRM model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values of overall treatment (i.e., each cycle \[Cycle 1 up to Cycle 30\]) was reported in this outcome measure.
Time frame: Baseline, overall treatment duration (Cycle 1 up to Cycle 30 [i.e.,116 weeks])
Population: Analysis was performed on safety population evaluable which includes all participants randomly assigned to study intervention, who took at least 1 dose of study intervention, completed the baseline and at least 1 post baseline on-treatment assessment. Here, 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Cognitive functioning | -0.9 score on a scale | Standard Error 1.6 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Pain | 1.1 score on a scale | Standard Error 1.9 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Physical functioning | -1.2 score on a scale | Standard Error 1.3 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Dyspnoea | 1.0 score on a scale | Standard Error 1.6 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Social functioning | -2.5 score on a scale | Standard Error 1.7 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Insomnia | -1.1 score on a scale | Standard Error 2.3 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Emotional functioning | -2.2 score on a scale | Standard Error 1.7 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Appetite loss | 2.4 score on a scale | Standard Error 2.3 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Fatigue | 1.1 score on a scale | Standard Error 1.9 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Constipation | -2.3 score on a scale | Standard Error 2 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Role functioning | -2.4 score on a scale | Standard Error 1.9 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Diarrhoea | 0.3 score on a scale | Standard Error 1.3 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Nausea and vomiting | 1.7 score on a scale | Standard Error 1.3 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Financial difficulties | 1.7 score on a scale | Standard Error 1.8 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | GHS/QoL | 1.8 score on a scale | Standard Error 1.6 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Financial difficulties | -2.0 score on a scale | Standard Error 1.8 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | GHS/QoL | 2.5 score on a scale | Standard Error 1.6 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Physical functioning | -3.1 score on a scale | Standard Error 1.3 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Role functioning | -3.0 score on a scale | Standard Error 1.8 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Emotional functioning | 3.0 score on a scale | Standard Error 1.6 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Cognitive functioning | -0.8 score on a scale | Standard Error 1.5 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Social functioning | -0.8 score on a scale | Standard Error 1.7 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Fatigue | 2.8 score on a scale | Standard Error 1.9 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Nausea and vomiting | 1.3 score on a scale | Standard Error 1.3 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Pain | 2.1 score on a scale | Standard Error 1.9 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Dyspnoea | 0.8 score on a scale | Standard Error 1.6 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Insomnia | -2.3 score on a scale | Standard Error 2.2 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Appetite loss | 1.2 score on a scale | Standard Error 2.3 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Constipation | 3.0 score on a scale | Standard Error 2 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores | Diarrhoea | 3.9 score on a scale | Standard Error 1.3 |
Secondary
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores
QLQ-BR23: disease-specific Health-related QOL assesses impact of breast cancer & side effects of treatment. EORTC-QLQ-BR23 contains 23 items: multi-item scales & single-item measures. 4 functional scales (body image, sexual functioning, sexual enjoyment, future perspective) & 4 scales related to symptoms of disease or treatment (arm symptoms, breast symptoms, systemic therapy side effects, & upset by hair loss). All items scored 1 (not at all) to 4 (very much). Scores of all scales transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional scales = better outcome; higher score for symptoms scales = higher symptom burden. LS mean and SE are derived from MMRM model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values of overall treatment (i.e., each cycle \[Cycle 1 up to Cycle 30\]) was reported.
Time frame: Baseline, overall treatment duration (Cycle 1 up to Cycle 30 [i.e.,116 weeks])
Population: Analysis was performed on Safety population evaluable. Here, 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Body image | 1.8 score on a scale | Standard Error 1.7 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Sexual functioning | -2.4 score on a scale | Standard Error 1.3 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Sexual enjoyment | -1.1 score on a scale | Standard Error 3 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Future perspective | 10.6 score on a scale | Standard Error 2.7 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Systemic therapy side effects | 0.2 score on a scale | Standard Error 1 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Breast symptoms | -0.4 score on a scale | Standard Error 1.3 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Arm symptoms | 1.8 score on a scale | Standard Error 1.7 |
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Upset by hair loss | -9.7 score on a scale | Standard Error 3.9 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Upset by hair loss | -10.6 score on a scale | Standard Error 3.7 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Body image | 2.2 score on a scale | Standard Error 1.6 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Systemic therapy side effects | 0.7 score on a scale | Standard Error 1 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Sexual functioning | -2.6 score on a scale | Standard Error 1.2 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Arm symptoms | 2.0 score on a scale | Standard Error 1.7 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Sexual enjoyment | 0.4 score on a scale | Standard Error 4.1 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Breast symptoms | -0.8 score on a scale | Standard Error 1.2 |
| Amcenestrant | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores | Future perspective | 12.0 score on a scale | Standard Error 2.6 |
Secondary
Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Health Utility Index Value
EQ-5D-5L: consists of 2 sections: EQ-5D-5L health state utility index (descriptive system) & VAS. The EQ-5D descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort & anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, & extreme problems. Response options are measured with 5-point Likert scale (for 5L version). The EQ-5D-5L responses are converted into single index utility score between 0 to 1, where higher score indicates better health state & lower score indicate worse health state. LS mean and SE are derived from MMRM model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from baseline values overall treatment (i.e., each cycle \[Cycle 1 up to Cycle 30\]) was reported in this outcome measure.
Time frame: Baseline, overall treatment duration (Cycle 1 up to Cycle 30 [i.e.,116 weeks])
Population: Analysis was performed on Safety population evaluable. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Health Utility Index Value | -0.0 score on a scale | Standard Error 0 |
| Amcenestrant | Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Health Utility Index Value | -0.0 score on a scale | Standard Error 0 |
Secondary
Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Visual Analog Scale (VAS) Score
EQ-5D-5L is a standardized measure of health status, provides a simple, generic measure of health for clinical and economic appraisal, and consists of 2 sections: the EQ-5D-5L health state utility index (descriptive system) and the EQ-5D-5L VAS. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. LS mean and SE are derived from MMRM model with change from baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value and stratifications factors as fixed effect. Average of LS mean change from Baseline values of overall treatment (i.e., each cycle \[Cycle 1 up to Cycle 30\]) was reported in this outcome measure.
Time frame: Baseline, overall treatment duration (Cycle 1 up to Cycle 30 [i.e.,116 weeks])
Population: Analysis was performed on Safety population evaluable. Here, overall number of participants analyzed signifies participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) | Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Visual Analog Scale (VAS) Score | 0.9 score on a scale | Standard Error 1.4 |
| Amcenestrant | Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Visual Analog Scale (VAS) Score | 0.2 score on a scale | Standard Error 1.4 |
Secondary
Duration of Response (DOR)
DOR is defined as time (in months) from first documented evidence of CR or PR until progressive disease (PD) determined by ICR as per RECIST 1.1 or death from any cause, whichever occurs first. For participants with ongoing response at the time of the analysis, DOR was censored at the date of the last valid disease assessment not showing documented progression performed before the initiation of a new anticancer treatment (if any). As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions.
Time frame: From the date of first response to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
Population: Analysis was performed on a subset of participants who had objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) | Duration of Response (DOR) | NA months |
| Amcenestrant | Duration of Response (DOR) | 15.1 months |
Secondary
Overall Survival (OS)
OS is defined as the time interval from the date of randomization to the date of documented death (due to any cause). In the absence of observation of death, survival time was censored to last date the participant is known to be alive or at the cut-off date, whichever comes first. Analysis was performed by Kaplan-Meier method.
Time frame: From randomization to the death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
Population: Analysis was performed on the ITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) | Overall Survival (OS) | NA months |
| Amcenestrant | Overall Survival (OS) | NA months |
Secondary
Percentage of Participants With Clinical Benefit
Clinical Benefit is defined as percentage of participants having a confirmed CR, PR, SD, or Non-CR/Non-PD for at least 24 weeks determined by ICR as per RECIST 1.1 from the date of randomization to the date of end of treatment. As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. Non-CR/Non-PD: persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions.
Time frame: From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
Population: Analysis was performed on the ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) | Percentage of Participants With Clinical Benefit | 29.3 percentage of participants |
| Amcenestrant | Percentage of Participants With Clinical Benefit | 27.3 percentage of participants |
Secondary
Percentage of Participants With Disease Control
Disease control is defined as percentage of participants having a confirmed CR, PR, or stable disease (SD) or Non-CR/Non-PD as BOR determined by ICR as per RECIST 1.1 from the date of randomization to the date of end of treatment. As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters. Non-CR/Non-PD: persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions.
Time frame: From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
Population: Analysis was performed on the ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) | Percentage of Participants With Disease Control | 53.7 percentage of participants |
| Amcenestrant | Percentage of Participants With Disease Control | 54.5 percentage of participants |
Secondary
Percentage of Participants With Objective Response
Objective response is defined as percentage of participants having a partial response (PR) or complete response (CR) according to the RECIST version 1.1 assessed by ICR. As per RECIST 1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
Population: Analysis was performed on the ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) | Percentage of Participants With Objective Response | 8.8 percentage of participants |
| Amcenestrant | Percentage of Participants With Objective Response | 11.9 percentage of participants |
Secondary
Pharmacokinetics: Plasma Concentrations of Amcenestrant
Amcenestrant plasma concentrations at specified time points are reported.
Time frame: Cycle 1 Day 1: 1.5 hours(h), 4h post-dose, Day 15: pre-dose, Cycle 2 Day 1: pre-dose, 1.5h, 4h, 8h post-dose, Cycle 3 Day 1: pre-dose, Cycle 4 Day 1: pre-dose, Cycle 6 Day 1: pre-dose
Population: Analysis was performed on Pharmacokinetic-evaluable population: all participant who were assigned to study intervention, took at least 1 dose of study intervention, had at least 1 available plasma concentration post treatment with adequate documentation of date and time of dosing and date and time of sampling. Here, 'number analyzed' = participants with available data for each specified category. Data for this outcome measure was not planned to be collected and analyzed for PCEM group arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) | Pharmacokinetics: Plasma Concentrations of Amcenestrant | Cycle 3 Day 1: Pre-dose | 593.6 nanograms per milliliter (ng/mL) | Standard Deviation 815.1 |
| Physician Choice Endocrine Monotherapy (PCEM) | Pharmacokinetics: Plasma Concentrations of Amcenestrant | Cycle 4 Day 1: Pre-dose | 661.5 nanograms per milliliter (ng/mL) | Standard Deviation 860.5 |
| Physician Choice Endocrine Monotherapy (PCEM) | Pharmacokinetics: Plasma Concentrations of Amcenestrant | Cycle 6 Day 1: Pre-dose | 531.5 nanograms per milliliter (ng/mL) | Standard Deviation 468.5 |
| Physician Choice Endocrine Monotherapy (PCEM) | Pharmacokinetics: Plasma Concentrations of Amcenestrant | Cycle 1 Day 1: 1.5h | 3185.7 nanograms per milliliter (ng/mL) | Standard Deviation 3145.2 |
| Physician Choice Endocrine Monotherapy (PCEM) | Pharmacokinetics: Plasma Concentrations of Amcenestrant | Cycle 1 Day 1: 4h | 4753.1 nanograms per milliliter (ng/mL) | Standard Deviation 3463.7 |
| Physician Choice Endocrine Monotherapy (PCEM) | Pharmacokinetics: Plasma Concentrations of Amcenestrant | Cycle 1 Day 15: Pre-dose | 516.4 nanograms per milliliter (ng/mL) | Standard Deviation 377.2 |
| Physician Choice Endocrine Monotherapy (PCEM) | Pharmacokinetics: Plasma Concentrations of Amcenestrant | Cycle 2 Day 1: Pre-dose | 479.1 nanograms per milliliter (ng/mL) | Standard Deviation 320.3 |
| Physician Choice Endocrine Monotherapy (PCEM) | Pharmacokinetics: Plasma Concentrations of Amcenestrant | Cycle 2 Day 1: 1.5h | 2719.6 nanograms per milliliter (ng/mL) | Standard Deviation 2374 |
| Physician Choice Endocrine Monotherapy (PCEM) | Pharmacokinetics: Plasma Concentrations of Amcenestrant | Cycle 2 Day 1: 4h | 3801.8 nanograms per milliliter (ng/mL) | Standard Deviation 2370.8 |
| Physician Choice Endocrine Monotherapy (PCEM) | Pharmacokinetics: Plasma Concentrations of Amcenestrant | Cycle 2 Day 1: 8h | 2303.8 nanograms per milliliter (ng/mL) | Standard Deviation 1411.4 |
Secondary
Progression Free Survival (PFS) According to Estrogen Receptor 1 Gene (ESR1) Mutation Status
PFS defined as the time (in months) interval from the date of randomization to the date of first documented tumor progression as per RECIST 1.1 assessed by ICR or death (due to any cause), whichever comes first. Progression as per RECIST 1.1: at least a 20 percent (%) increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. The mutation status (wild type, mutant) of twelve specific mutations of the ESR1 gene was determined by multiplex droplet digital polymerase chain reaction (ddPCR), including their mutant frequency and concentration. Here, PFS is reported based on the ESR1 mutation status of participants: wild type and mutants. ESR1 was the gene encoding estrogen receptor alpha. ESR1 mutant type breast cancer was a disease where the ESR1 gene had a mutation (i.e., a type of error). ESR1 wild type breast cancer was a disease where the ESR1 gene was normal without a mutation. Analysis was performed by Kaplan-Meier method.
Time frame: From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (maximum duration: 116 weeks)
Population: Analysis was performed on the ITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure and number analyzed = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) | Progression Free Survival (PFS) According to Estrogen Receptor 1 Gene (ESR1) Mutation Status | Mutated | 2.0 months |
| Physician Choice Endocrine Monotherapy (PCEM) | Progression Free Survival (PFS) According to Estrogen Receptor 1 Gene (ESR1) Mutation Status | Wild type | 3.9 months |
| Amcenestrant | Progression Free Survival (PFS) According to Estrogen Receptor 1 Gene (ESR1) Mutation Status | Mutated | 3.7 months |
| Amcenestrant | Progression Free Survival (PFS) According to Estrogen Receptor 1 Gene (ESR1) Mutation Status | Wild type | 3.5 months |
Secondary
Within-Participant Steady State Ctrough of Amcenestrant
Within-participant Steady state Ctrough was defined as the median value of the Ctrough across study using plasma concentration of predose samples at Cycle 1 Day 15 and Day 1 of Cycle 2, 3, 4 and 6 for each individual participant. Average (mean) of all calculated Ctrough values for all participants across study (Cycle 1 Day 15 and Day 1 of Cycle 2, 3, 4 and 6 ) was derived and reported in this outcome measure.
Time frame: Predose on Cycle 1 Day 15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 4 Day 1; Cycle 6 Day 1
Population: Analysis was performed on Pharmacokinetic-evaluable population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure. Data for this outcome measure was not planned to be collected and analyzed for PCEM group arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Physician Choice Endocrine Monotherapy (PCEM) | Within-Participant Steady State Ctrough of Amcenestrant | 491.35 ng/mL | Standard Deviation 316.51 |