Trial Outcomes & Findings for Amcenestrant (SAR439859) Plus Palbociclib as First Line Therapy for Patients With ER (+) HER2(-) Advanced Breast Cancer (NCT NCT04478266)

Last Updated: 2025-09-11

Results Overview

PFS was defined as the time interval (in months) 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 local radiologist or investigator, 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.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

1068 participants

Primary outcome timeframe

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: 81 weeks)

Results posted on

2025-09-11

Participant Flow

The study was conducted at 249 active sites in 30 countries. A total of 1277 participants were screened between 14 October 2020 and 11 November 2021, of which 209 were screen failures. Screen failures were mainly due to not meeting selection criteria.

A total of 1068 participants were randomized, of which 2 participants were randomized but not exposed to study treatment. Randomization was stratified by De-novo metastatic disease (Yes or No); postmenopausal women (Yes or No); visceral metastasis defined by at least 1 liver, lung, brain metastasis, pleural, or peritoneal involvement (Yes or No).

Participant milestones

Participant milestones
Measure	Letrozole + Palbociclib Participants received letrozole 2.5 milligram (mg) capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg orally (PO), once daily (QD) from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death, or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Overall Study STARTED	534	534
Overall Study Treated	533	533
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	534	534

Reasons for withdrawal

Reasons for withdrawal
Measure	Letrozole + Palbociclib Participants received letrozole 2.5 milligram (mg) capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg orally (PO), once daily (QD) from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death, or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Overall Study Adverse Event	20	21
Overall Study Progressive disease	146	168
Overall Study Poor compliance to protocol	1	0
Overall Study Withdrawal by Subject	19	16
Overall Study Data Monitoring Committee recommendation due to negative interim analysis	309	286
Overall Study Study terminated by sponsor	33	35
Overall Study Other: unspecified	5	7
Overall Study Randomized but not treated	1	1

Baseline Characteristics

Amcenestrant (SAR439859) Plus Palbociclib as First Line Therapy for Patients With ER (+) HER2(-) Advanced Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Letrozole + Palbociclib n=533 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg, PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=533 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).	Total n=1066 Participants Total of all reporting groups
Age, Continuous	57.3 years STANDARD_DEVIATION 12.3 • n=5 Participants	57.8 years STANDARD_DEVIATION 12.1 • n=7 Participants	57.6 years STANDARD_DEVIATION 12.2 • n=5 Participants
Sex: Female, Male Female	529 Participants n=5 Participants	524 Participants n=7 Participants	1053 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	9 Participants n=7 Participants	13 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	179 Participants n=5 Participants	175 Participants n=7 Participants	354 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Black or African American	10 Participants n=5 Participants	10 Participants n=7 Participants	20 Participants n=5 Participants
Race (NIH/OMB) White	306 Participants n=5 Participants	304 Participants n=7 Participants	610 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	36 Participants n=5 Participants	41 Participants n=7 Participants	77 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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: 81 weeks)

Population: Analysis was performed on the ITT population which included all enrolled participants (i.e., who signed the informed consent form and for whom there was a confirmation of successful allocation of a randomization number by Interactive Response Technology \[IRT\].

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=534 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=534 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Progression-free Survival (PFS)	16.6 months Interval 14.1 to Upper limit of 95% confidence interval (CI) was not estimable due to the smaller number of participants with events.	14.1 months Interval 13.9 to Upper limit of 95% confidence interval (CI) was not estimable due to the smaller number of participants with events.

SECONDARY outcome

Timeframe: From randomization to the death due to any cause or data cut-off date, whichever comes first (maximum duration: 81 weeks)

Population: Analysis was performed on the ITT population.

OS was defined as the interval (in months) 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 was known to be alive or at the cut-off date, whichever comes first. Analysis was performed by Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=534 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=534 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Overall Survival (OS)	NA months Median, upper limit and lower limit of 95% CI were not estimable due to the smaller number of participants with events.	NA months Median, upper limit and lower limit of 95% CI were not estimable due to the smaller number of participants with events.

SECONDARY outcome

Timeframe: Month 12

Population: Analysis was performed on the ITT population.

Percentage of participants who were disease progression-free at Month 12 after randomization were reported in this outcome measure. PFS was defined as the time interval (in months) from the date of randomization to the date of first documented tumor progression as per RECIST 1.1 assessed by local radiologist or investigator, 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. The PFS rate at Month 12 was estimated using the Kaplan-Meier method and provided an estimation of the percentage of participants who were disease progression-free at Month 12 after randomization.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=534 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=534 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
12-month Progression-free Survival (PFS) Rate	68.2 percentage of participants Interval 61.2 to 74.2	65.5 percentage of participants Interval 59.1 to 71.1

SECONDARY outcome

Timeframe: 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: 81 weeks)

Population: Analysis was performed on the ITT population.

Objective response was defined as percentage of participants having a partial response (PR) or complete response (CR) according to the RECIST version 1.1 assessed by investigator. 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.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=534 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=534 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Percentage of Participants With Objective Response	42.3 percentage of participants Interval 38.1 to 46.6	32.2 percentage of participants Interval 28.3 to 36.4

SECONDARY outcome

Timeframe: From the date of first response of CR or PR until disease progression or death, or start of any anti-cancer therapy or data cut-off date, whichever comes first (maximum duration: 81 weeks)

Population: Analysis was performed on a subset of participants who had objective response.

DOR was defined as time (in months) from first documented evidence of CR or PR until disease progression determined by investigator as per RECIST 1.1, or start of any anti-cancer therapy, 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 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: 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. Analysis was performed by Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=226 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=172 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Duration of Response (DOR)	14.0 months Interval 11.1 to Upper limit of 95% CI was not estimable due to small number of progression events or death.	NA months Interval 11.4 to Median and upper limit of 95% CI was not estimable due to the small number of progression events or death.

SECONDARY outcome

Timeframe: From randomization until disease progression, or death, or data cut-off date, whichever comes first (maximum duration: 81 weeks)

Population: Analysis was performed on the ITT population.

Clinical Benefit was defined as the percentage of participants having a confirmed CR, PR, or stable disease (SD) for at least 24 weeks determined by investigator as per RECIST 1.1, from date of randomization until disease progression, or death, or data cut-off date, or initiation of post treatment anti-cancer therapy, whichever occurs first. As per RECIST 1.1; CR was defined as disappearance of all target, non-target lesions \& 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 smallest sum diameters. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=534 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=534 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Percentage of Participants With Clinical Benefit	82.4 percentage of participants Interval 78.9 to 85.5	76.0 percentage of participants Interval 72.2 to 79.6

SECONDARY outcome

Timeframe: From randomization to date first documented disease progression on the next systemic anti-cancer therapy, or death due to any cause, or data cut-off date, whichever comes first (maximum duration: 81 weeks)

Population: Analysis was performed on the ITT population.

PFS2 was defined as the time interval (in months) from the date of randomization to the date of first documentation of PD on the next systemic anti-cancer therapy according to investigator, or death due to any cause in the absence of documented PD on the next systemic anti-cancer therapy, whichever occurs first. PD was defined as at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=534 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=534 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Progression-free Survival on Next Line of Therapy (PFS2)	NA months Median, upper and lower limit of 95% CI was not estimable due to the smaller number of participants with events.	NA months Median, upper and lower limit of 95% CI was not estimable due to the smaller number of participants with events.

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 3 hours (hr) post-dose, Cycle 1 Day 15: pre-dose, Cycle 2 Day 1: pre-dose, 3 hr post-dose, Cycle 2 Day 15: pre-dose, Cycle 3 Day 1: pre-dose, Cycle 4 Day 1: pre-dose, Cycle 7 Day 1: pre-dose, Cycle 10 Day 1: pre-dose

Population: Analysis was performed on the Pharmacokinetic-evaluable (amcenestrant) population that included all participants who took at least 1 dose of study intervention, and with at least one evaluable plasma concentration of amcenestrant post-treatment. 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.

Amcenestrant plasma concentrations at specified time points were reported. Data for this outcome measure was not planned to be collected and analyzed for Letrozole+Palbociclib arm as pre-specified in protocol.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=531 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Pharmacokinetics: Plasma Concentrations of Amcenestrant Cycle 10 Day 1: pre-dose	310.9 nanograms per milliliter Standard Deviation 253.3	—
Pharmacokinetics: Plasma Concentrations of Amcenestrant Cycle 1 Day 1: 3 hr post-dose	2890.0 nanograms per milliliter Standard Deviation 1783.8	—
Pharmacokinetics: Plasma Concentrations of Amcenestrant Cycle 1 Day 15: pre-dose	399.5 nanograms per milliliter Standard Deviation 575.0	—
Pharmacokinetics: Plasma Concentrations of Amcenestrant Cycle 2 Day 1: pre-dose	387.5 nanograms per milliliter Standard Deviation 685.6	—
Pharmacokinetics: Plasma Concentrations of Amcenestrant Cycle 2 Day 1: 3 hr post-dose	2729.3 nanograms per milliliter Standard Deviation 1604.4	—
Pharmacokinetics: Plasma Concentrations of Amcenestrant Cycle 2 Day 15: pre-dose	361.3 nanograms per milliliter Standard Deviation 572.8	—
Pharmacokinetics: Plasma Concentrations of Amcenestrant Cycle 3 Day 1: pre-dose	303.4 nanograms per milliliter Standard Deviation 315.7	—
Pharmacokinetics: Plasma Concentrations of Amcenestrant Cycle 4 Day 1: pre-dose	349.3 nanograms per milliliter Standard Deviation 385.3	—
Pharmacokinetics: Plasma Concentrations of Amcenestrant Cycle 7 Day 1: pre-dose	337.5 nanograms per milliliter Standard Deviation 432.9	—

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 3 hr post-dose, Cycle 1 Day 15: pre-dose, Cycle 2 Day 1: pre-dose, 3 hr post-dose, Cycle 2 Day 15: pre-dose, Cycle 3 Day 1: pre-dose, Cycle 4 Day 1: pre-dose, Cycle 7 Day 1: pre-dose, Cycle 10 Day 1: pre-dose

Population: Analysis was performed on the Pharmacokinetic-evaluable (palbociclib) population that included all participants who took at least 1 dose of study intervention, and with at least one evaluable plasma concentration of palbociclib post-treatment. Here, 'Number analyzed' = participants with available data for each specified category.

Palbociclib plasma concentrations at specified time points were reported.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=532 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=532 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Pharmacokinetics: Plasma Concentrations of Palbociclib Cycle 1 Day 1: 3 hr post-dose	36.265 nanograms per milliliter Standard Deviation 31.110	37.780 nanograms per milliliter Standard Deviation 31.005
Pharmacokinetics: Plasma Concentrations of Palbociclib Cycle 1 Day 15: pre-dose	82.541 nanograms per milliliter Standard Deviation 38.671	45.903 nanograms per milliliter Standard Deviation 20.086
Pharmacokinetics: Plasma Concentrations of Palbociclib Cycle 2 Day 1: pre-dose	3.409 nanograms per milliliter Standard Deviation 8.498	2.159 nanograms per milliliter Standard Deviation 7.368
Pharmacokinetics: Plasma Concentrations of Palbociclib Cycle 2 Day 1: 3 hr post-dose	30.234 nanograms per milliliter Standard Deviation 26.967	27.144 nanograms per milliliter Standard Deviation 24.667
Pharmacokinetics: Plasma Concentrations of Palbociclib Cycle 2 Day 15: pre-dose	72.176 nanograms per milliliter Standard Deviation 35.210	42.882 nanograms per milliliter Standard Deviation 18.081
Pharmacokinetics: Plasma Concentrations of Palbociclib Cycle 3 Day 1: pre-dose	4.301 nanograms per milliliter Standard Deviation 11.796	1.615 nanograms per milliliter Standard Deviation 4.283
Pharmacokinetics: Plasma Concentrations of Palbociclib Cycle 4 Day 1: pre-dose	4.767 nanograms per milliliter Standard Deviation 17.787	1.390 nanograms per milliliter Standard Deviation 3.052
Pharmacokinetics: Plasma Concentrations of Palbociclib Cycle 7 Day 1: pre-dose	2.716 nanograms per milliliter Standard Deviation 2.058	1.461 nanograms per milliliter Standard Deviation 1.722
Pharmacokinetics: Plasma Concentrations of Palbociclib Cycle 10 Day 1: pre-dose	3.793 nanograms per milliliter Standard Deviation 7.675	1.489 nanograms per milliliter Standard Deviation 1.155

SECONDARY outcome

Timeframe: Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks])

Population: Analysis was performed on safety population. Here, 'Number analyzed' = participants with available data for each specified category.

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) \& 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) were 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 \[Cycle 1 up to Cycle 21\]) for each domain was reported in this outcome measure.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=533 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=533 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores GHS/QoL	2.8 score on a scale Standard Error 0.6	3.1 score on a scale Standard Error 0.6
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores Physical functioning	2.3 score on a scale Standard Error 0.5	2.6 score on a scale Standard Error 0.6
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores Role functioning	1.8 score on a scale Standard Error 0.7	2.0 score on a scale Standard Error 0.7
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores Emotional functioning	4.2 score on a scale Standard Error 0.6	4.1 score on a scale Standard Error 0.7
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 0.6	-1.2 score on a scale Standard Error 0.6
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores Social functioning	2.2 score on a scale Standard Error 0.7	4.4 score on a scale Standard Error 0.8
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores Fatigue	-1.6 score on a scale Standard Error 0.7	-2.0 score on a scale Standard Error 0.7
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 0.4	-0.6 score on a scale Standard Error 0.4
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores Pain	-5.8 score on a scale Standard Error 0.7	-6.8 score on a scale Standard Error 0.7
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores Dyspnea	-1.1 score on a scale Standard Error 0.7	-0.7 score on a scale Standard Error 0.7
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores Insomnia	-2.9 score on a scale Standard Error 0.9	-3.9 score on a scale Standard Error 0.9
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores Appetite loss	-3.0 score on a scale Standard Error 0.7	-2.7 score on a scale Standard Error 0.7
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores Constipation	0.1 score on a scale Standard Error 0.8	0.0 score on a scale Standard Error 0.9
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores Diarrhea	-0.4 score on a scale Standard Error 0.4	0.4 score on a scale Standard Error 0.4
Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores Financial difficulties	-5.1 score on a scale Standard Error 0.8	-4.0 score on a scale Standard Error 0.8

SECONDARY outcome

Timeframe: Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks])

Population: Analysis was performed on safety population. Here, 'Number analyzed' = participants with available data for each specified category.

QLQ-BR23: disease-specific Health-related QOL assesses breast cancer impact \& side effects of treatment. EORTCQLQ- 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 0-100. Higher score for functional scales=better outcome; higher score for symptoms scales=higher symptom burden. LS mean \& SE were derived from MMRM model with change from Baseline values as response variable, treatment, time, treatment-by-time interaction, Baseline value \& stratifications factors as fixed effect. Average of LS mean change from Baseline values of overall treatment (i.e., each cycle \[Cycle 1 up to Cycle 21\]) for each domain was reported.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=533 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=533 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
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	1.3 score on a scale Standard Error 0.7	1.1 score on a scale Standard Error 0.7
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	-1.4 score on a scale Standard Error 0.6	-1.5 score on a scale Standard Error 0.6
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	-10.4 score on a scale Standard Error 1.9	-8.7 score on a scale Standard Error 1.9
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	11.6 score on a scale Standard Error 1.0	10.8 score on a scale Standard Error 1.0
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	4.9 score on a scale Standard Error 0.5	3.7 score on a scale Standard Error 0.5
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	-7.6 score on a scale Standard Error 0.5	-7.0 score on a scale Standard Error 0.5
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	-1.9 score on a scale Standard Error 0.6	-1.8 score on a scale Standard Error 0.6
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	-2.7 score on a scale Standard Error 2.2	-0.2 score on a scale Standard Error 2.5

SECONDARY outcome

Timeframe: Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks])

Population: Analysis was performed on safety population. Here, 'Number analyzed' = participants with available data for each specified category.

EORTC QLQ-BR45: comprised of all 23 items from the QLQ-BR23 plus an additional 22 items assessing endocrine therapy symptoms (10 items), endocrine sexual symptoms (4 items), breast satisfaction (2 items), and skin mucosis symptoms (6 items). 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 Mixed Model Repeated Measures (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 \[Cycle 1 up to Cycle 21\]) for each domain (endocrine therapy symptoms, endocrine sexual symptoms, breast satisfaction and skin mucosis symptoms) was reported.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=533 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=533 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC QLQ-BR45) Domain Scores Breast Satisfaction	-1.7 score on a scale Standard Error 1.2	1.0 score on a scale Standard Error 1.3
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC QLQ-BR45) Domain Scores Endocrine Sexual Symptoms	4.8 score on a scale Standard Error 0.8	2.3 score on a scale Standard Error 0.8
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC QLQ-BR45) Domain Scores Endocrine Therapy Symptoms	1.5 score on a scale Standard Error 0.6	1.2 score on a scale Standard Error 0.6
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC QLQ-BR45) Domain Scores Skin Mucosis Symptoms	3.5 score on a scale Standard Error 0.5	2.5 score on a scale Standard Error 0.5

SECONDARY outcome

Timeframe: Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks])

Population: Analysis was performed on safety population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.

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 \[Cycle 1 up to Cycle 21\]) for VAS was reported in this outcome measure.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=492 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=489 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
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	3.2 score on a scale Standard Error 0.5	3.8 score on a scale Standard Error 0.5

SECONDARY outcome

Timeframe: Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks])

Population: Analysis was performed on safety population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.

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 were 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 \[Cycle 1 up to Cycle 21\]) for health utility index value score was reported in this outcome measure.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=492 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=489 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
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 Score	0.0 score on a scale Standard Error 0.0	0.0 score on a scale Standard Error 0.0

SECONDARY outcome

Timeframe: From randomization to the start date of the first chemotherapy (maximum duration: 81 weeks)

Population: Analysis was performed on the ITT population.

Time to chemotherapy was defined as the time interval (in months) from the date of randomization to the start date of the first chemotherapy after disease progression.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=534 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=534 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Time to First Chemotherapy	NA months Median, upper limit and lower limit of 95% CI was not estimable due to lower number of participants with events.	NA months Median, upper limit and lower limit of 95% CI was not estimable due to lower number of participants with events.

SECONDARY outcome

Timeframe: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: 112 weeks)

Population: Analysis was performed on safety population. Here, 'Number analyzed' = participants with available data for each specified category.

Hematological parameters assessed were anemia, lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, platelet count decreased. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 5.0 (NCI-CTCAE v 5.0), where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. Treatment period was defined as the time from the first dose of study treatments up to 30 days after last dose of study treatment.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=533 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=533 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Number of Participants With Hematological Abnormalities During the Treatment Period Lymphocyte count decreased: Grade 3	46 Participants	48 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Anemia: Grade 3	22 Participants	17 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Lymphocyte count decreased: Grade 4	23 Participants	22 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Neutrophil count decreased: Grade 1	22 Participants	45 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Neutrophil count decreased: Grade 2	150 Participants	217 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Neutrophil count decreased: Grade 3	277 Participants	199 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Neutrophil count decreased: Grade 4	70 Participants	21 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Anemia: Grade 1	309 Participants	302 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Anemia: Grade 2	108 Participants	78 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period White blood cell decreased: Grade 1	81 Participants	146 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period White blood cell decreased: Grade 2	279 Participants	267 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period White blood cell decreased: Grade 3	163 Participants	95 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period White blood cell decreased: Grade 4	7 Participants	3 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Platelet count decreased: Grade 1	285 Participants	220 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Platelet count decreased: Grade 2	30 Participants	12 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Platelet count decreased: Grade 3	18 Participants	8 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Platelet count decreased: Grade 4	8 Participants	10 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Anemia: Grade 4	0 Participants	0 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Lymphocyte count decreased: Grade 1	98 Participants	101 Participants
Number of Participants With Hematological Abnormalities During the Treatment Period Lymphocyte count decreased: Grade 2	138 Participants	124 Participants

SECONDARY outcome

Timeframe: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: 112 weeks)

Population: Analysis was performed on safety population. Here, 'Number analyzed' = participants with available data for each specified category.

Liver Function parameters assessed were aspartate aminotransferase increased, alanine aminotransferase increased, alkaline phosphatase increased, total bilirubin increased, gamma-glutamyl transferase increased. Parameters were assessed as per the NCI-CTCAE v 5.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs. Treatment period was defined as the time from the first dose of study treatments up to 30 days after last dose of study treatment. Participants with Grade 3 and 4 liver function abnormalities were reported in this outcome measure.

Outcome measures

Outcome measures
Measure	Letrozole + Palbociclib n=533 Participants Participants received letrozole 2.5 mg capsule along with amcenestrant-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 112 weeks).	Amcenestrant + Palbociclib n=533 Participants Participants received amcenestrant 200 mg tablet along with letrozole-matching placebo once daily, continuously and palbociclib 125 mg PO, QD from Day 1 to Day 21 of each 28-day treatment cycle until disease progression, death or study cut-off date, whichever comes first (maximum exposure: 109 weeks).
Number of Participants With Liver Function Abnormalities of Grade 3 and 4 During the Treatment Period Aspartate aminotransferase increased: Grade 3	9 Participants	23 Participants
Number of Participants With Liver Function Abnormalities of Grade 3 and 4 During the Treatment Period Aspartate aminotransferase increased: Grade 4	0 Participants	1 Participants
Number of Participants With Liver Function Abnormalities of Grade 3 and 4 During the Treatment Period Alanine aminotransferase increased: Grade 3	12 Participants	32 Participants
Number of Participants With Liver Function Abnormalities of Grade 3 and 4 During the Treatment Period Alanine aminotransferase increased: Grade 4	1 Participants	3 Participants
Number of Participants With Liver Function Abnormalities of Grade 3 and 4 During the Treatment Period Alkaline phosphatase increased: Grade 3	3 Participants	1 Participants
Number of Participants With Liver Function Abnormalities of Grade 3 and 4 During the Treatment Period Alkaline phosphatase increased: Grade 4	0 Participants	0 Participants
Number of Participants With Liver Function Abnormalities of Grade 3 and 4 During the Treatment Period Total bilirubin increased: Grade 3	3 Participants	5 Participants
Number of Participants With Liver Function Abnormalities of Grade 3 and 4 During the Treatment Period Total bilirubin increased: Grade 4	0 Participants	0 Participants
Number of Participants With Liver Function Abnormalities of Grade 3 and 4 During the Treatment Period Gamma-GT increased: Grade 3	9 Participants	20 Participants
Number of Participants With Liver Function Abnormalities of Grade 3 and 4 During the Treatment Period Gamma-GT increased: Grade 4	0 Participants	1 Participants

Adverse Events

Letrozole + Palbociclib

Serious events: 68 serious events

Other events: 448 other events

Deaths: 41 deaths

Amcenestrant + Palbociclib

Serious events: 77 serious events

Other events: 412 other events

Deaths: 45 deaths

Serious adverse events

Other adverse events

Additional Information

Trial Transparency Team

Sanofi aventis recherche & développement

Phone: 800-633-1610

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.
Publication restrictions are in place

Restriction type: OTHER