Amcenestrant (SAR439859) Plus Palbociclib as First Line Therapy for Patients With ER (+) HER2(-) Advanced Breast Cancer (AMEERA-5)

• ClinicalTrials.gov Identifier: NCT04478266
• Recruitment Status: Terminated
• First Posted: July 20, 2020
• Results First Posted: July 6, 2023
• Last Update Posted: December 8, 2023
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Drug: Amcenestrant-matching placebo; Drug: SAR439859; Drug: Palbociclib; Drug: Letrozole; Drug: Goserelin; Drug: Letrozole-matching placebo
• Enrollment: 1068

Participant Flow

Recruitment Details	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.
Pre-assignment Details	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).

Arm/Group Title	Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description	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).	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).
Period Title: Overall Study
Started	534	534
Treated	533	533
Completed	0	0
Not Completed	534	534
Reason Not Completed
Adverse Event	20	21
Progressive disease	146	168
Poor compliance to protocol	1	0
Withdrawal by Subject	19	16
Data Monitoring Committee recommendation due to negative interim analysis	309	286
Study terminated by sponsor	33	35
Other: unspecified	5	7
Randomized but not treated	1	1

Baseline Characteristics

Arm/Group Title		Letrozole + Palbociclib	Amcenestrant + Palbociclib	Total
Arm/Group Description		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).	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 of all reporting groups
Overall Number of Baseline Participants		533	533	1066
Baseline Analysis Population Description		Analysis was performed on safety population which included all participants randomly assigned to study intervention and who took at least 1 dose of study intervention, analyzed according to the treatment arm they actually received.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	533 participants	533 participants	1066 participants
		57.3 (12.3)	57.8 (12.1)	57.6 (12.2)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	533 participants	533 participants	1066 participants
	Female	529 99.2%	524 98.3%	1053 98.8%
	Male	4 0.8%	9 1.7%	13 1.2%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	533 participants	533 participants	1066 participants
	American Indian or Alaska Native	0 0.0%	1 0.2%	1 0.1%
	Asian	179 33.6%	175 32.8%	354 33.2%
	Native Hawaiian or Other Pacific Islander	1 0.2%	1 0.2%	2 0.2%
	Black or African American	10 1.9%	10 1.9%	20 1.9%
	White	306 57.4%	304 57.0%	610 57.2%
	More than one race	1 0.2%	1 0.2%	2 0.2%
	Unknown or Not Reported	36 6.8%	41 7.7%	77 7.2%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	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.
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: 81 weeks)

Outcome Measure Data

Analysis Population Description

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].

Arm/Group Title	Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:	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).	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 Number of Participants Analyzed	534	534
Median (95% Confidence Interval); Unit of Measure: months
	16.6 [1]; (14.1 to NA)	14.1 [1]; (13.9 to NA)

[1]

Upper limit of 95% confidence interval (CI) was not estimable due to the smaller number of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letrozole + Palbociclib, Amcenestrant + Palbociclib
	Comments	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 were reported and continued when previous outcome measure was statistically significant at one-sided 2.5% for the primary and the first secondary outcome.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9304
	Comments	One-sided p-value based on Stratified log-rank test. Threshold for statistical significance at 0.025 level.
	Method	Stratified Log-Rank test
	Comments	Stratified on presence of De-novo metastatic disease, Postmenopausal women and Visceral metastasis according to IRT.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.209
	Confidence Interval	(2-Sided) 95%; 0.939 to 1.557
	Estimation Comments	Letrozole + Palbociclib versus Amcenestrant + Palbociclib

2. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	From randomization to the death due to any cause or data cut-off date, whichever comes first (maximum duration: 81 weeks)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the ITT population.

Arm/Group Title	Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:	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).	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 Number of Participants Analyzed	534	534
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Median, upper limit and lower limit of 95% CI were not estimable due to the smaller number of participants with events.

3. Secondary Outcome

Title	12-month Progression-free Survival (PFS) Rate
Description	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.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

Analysis was performed on the ITT population.

Arm/Group Title	Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:	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).	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 Number of Participants Analyzed	534	534
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	68.2; (61.2 to 74.2)	65.5; (59.1 to 71.1)

4. Secondary Outcome

Title	Percentage of Participants With Objective Response
Description	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.
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: 81 weeks)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the ITT population.

Arm/Group Title	Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:	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).	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 Number of Participants Analyzed	534	534
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	42.3; (38.1 to 46.6)	32.2; (28.3 to 36.4)

5. Secondary Outcome

Title	Duration of Response (DOR)
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:	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).	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 Number of Participants Analyzed	226	172
Median (95% Confidence Interval); Unit of Measure: months
	14.0 [1]; (11.1 to NA)	NA [2]; (11.4 to NA)

[1]

Upper limit of 95% CI was not estimable due to small number of progression events or death.

[2]

Median and upper limit of 95% CI was not estimable due to the small number of progression events or death.

6. Secondary Outcome

Title	Percentage of Participants With Clinical Benefit
Description	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.
Time Frame	From randomization until disease progression, or death, or data cut-off date, whichever comes first (maximum duration: 81 weeks)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the ITT population.

Arm/Group Title	Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:	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).	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 Number of Participants Analyzed	534	534
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	82.4; (78.9 to 85.5)	76.0; (72.2 to 79.6)

7. Secondary Outcome

Title	Progression-free Survival on Next Line of Therapy (PFS2)
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the ITT population.

Arm/Group Title	Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:	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).	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 Number of Participants Analyzed	534	534
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Median, upper and lower limit of 95% CI was not estimable due to the smaller number of participants with events.

8. Secondary Outcome

Title	Pharmacokinetics: Plasma Concentrations of Amcenestrant
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Amcenestrant + Palbociclib
Arm/Group Description:		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 Number of Participants Analyzed		531
Mean (Standard Deviation); Unit of Measure: nanograms per milliliter
Cycle 1 Day 1: 3 hr post-dose	Number Analyzed	473 participants
		2890.0 (1783.8)
Cycle 1 Day 15: pre-dose	Number Analyzed	283 participants
		399.5 (575.0)
Cycle 2 Day 1: pre-dose	Number Analyzed	255 participants
		387.5 (685.6)
Cycle 2 Day 1: 3 hr post-dose	Number Analyzed	441 participants
		2729.3 (1604.4)
Cycle 2 Day 15: pre-dose	Number Analyzed	253 participants
		361.3 (572.8)
Cycle 3 Day 1: pre-dose	Number Analyzed	215 participants
		303.4 (315.7)
Cycle 4 Day 1: pre-dose	Number Analyzed	169 participants
		349.3 (385.3)
Cycle 7 Day 1: pre-dose	Number Analyzed	162 participants
		337.5 (432.9)
Cycle 10 Day 1: pre-dose	Number Analyzed	118 participants
		310.9 (253.3)

9. Secondary Outcome

Title	Pharmacokinetics: Plasma Concentrations of Palbociclib
Description	Palbociclib plasma concentrations at specified time points were reported.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:		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).	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 Number of Participants Analyzed		532	532
Mean (Standard Deviation); Unit of Measure: nanograms per milliliter
Cycle 1 Day 1: 3 hr post-dose	Number Analyzed	479 participants	472 participants
		36.265 (31.110)	37.780 (31.005)
Cycle 1 Day 15: pre-dose	Number Analyzed	264 participants	274 participants
		82.541 (38.671)	45.903 (20.086)
Cycle 2 Day 1: pre-dose	Number Analyzed	201 participants	227 participants
		3.409 (8.498)	2.159 (7.368)
Cycle 2 Day 1: 3 hr post-dose	Number Analyzed	316 participants	385 participants
		30.234 (26.967)	27.144 (24.667)
Cycle 2 Day 15: pre-dose	Number Analyzed	237 participants	247 participants
		72.176 (35.210)	42.882 (18.081)
Cycle 3 Day 1: pre-dose	Number Analyzed	183 participants	192 participants
		4.301 (11.796)	1.615 (4.283)
Cycle 4 Day 1: pre-dose	Number Analyzed	131 participants	150 participants
		4.767 (17.787)	1.390 (3.052)
Cycle 7 Day 1: pre-dose	Number Analyzed	143 participants	142 participants
		2.716 (2.058)	1.461 (1.722)
Cycle 10 Day 1: pre-dose	Number Analyzed	97 participants	102 participants
		3.793 (7.675)	1.489 (1.155)

10. Secondary Outcome

Title	Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Domain Scores
Description	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.
Time Frame	Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks])

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:		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).	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 Number of Participants Analyzed		533	533
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
GHS/QoL	Number Analyzed	491 participants	485 participants
		2.8 (0.6)	3.1 (0.6)
Physical functioning	Number Analyzed	488 participants	484 participants
		2.3 (0.5)	2.6 (0.6)
Role functioning	Number Analyzed	490 participants	482 participants
		1.8 (0.7)	2.0 (0.7)
Emotional functioning	Number Analyzed	490 participants	484 participants
		4.2 (0.6)	4.1 (0.7)
Cognitive functioning	Number Analyzed	491 participants	485 participants
		-0.8 (0.6)	-1.2 (0.6)
Social functioning	Number Analyzed	489 participants	485 participants
		2.2 (0.7)	4.4 (0.8)
Fatigue	Number Analyzed	490 participants	484 participants
		-1.6 (0.7)	-2.0 (0.7)
Nausea and vomiting	Number Analyzed	485 participants	478 participants
		-1.3 (0.4)	-0.6 (0.4)
Pain	Number Analyzed	491 participants	485 participants
		-5.8 (0.7)	-6.8 (0.7)
Dyspnea	Number Analyzed	488 participants	480 participants
		-1.1 (0.7)	-0.7 (0.7)
Insomnia	Number Analyzed	490 participants	483 participants
		-2.9 (0.9)	-3.9 (0.9)
Appetite loss	Number Analyzed	485 participants	478 participants
		-3.0 (0.7)	-2.7 (0.7)
Constipation	Number Analyzed	486 participants	477 participants
		0.1 (0.8)	0.0 (0.9)
Diarrhea	Number Analyzed	490 participants	480 participants
		-0.4 (0.4)	0.4 (0.4)
Financial difficulties	Number Analyzed	488 participants	485 participants
		-5.1 (0.8)	-4.0 (0.8)

11. Secondary Outcome

Title	Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC-QLQ-BR23) Domain Scores
Description	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.
Time Frame	Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks])

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:		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).	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 Number of Participants Analyzed		533	533
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
Body image	Number Analyzed	463 participants	464 participants
		1.3 (0.7)	1.1 (0.7)
Sexual functioning	Number Analyzed	451 participants	450 participants
		-1.4 (0.6)	-1.5 (0.6)
Sexual enjoyment	Number Analyzed	101 participants	98 participants
		-10.4 (1.9)	-8.7 (1.9)
Future perspective	Number Analyzed	467 participants	465 participants
		11.6 (1.0)	10.8 (1.0)
Systemic therapy side effects	Number Analyzed	466 participants	466 participants
		4.9 (0.5)	3.7 (0.5)
Breast symptoms	Number Analyzed	466 participants	465 participants
		-7.6 (0.5)	-7.0 (0.5)
Arm symptoms	Number Analyzed	466 participants	466 participants
		-1.9 (0.6)	-1.8 (0.6)
Upset by hair loss	Number Analyzed	89 participants	75 participants
		-2.7 (2.2)	-0.2 (2.5)

12. Secondary Outcome

Title	Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Specific Module (EORTC QLQ-BR45) Domain Scores
Description	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.
Time Frame	Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks])

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:		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).	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 Number of Participants Analyzed		533	533
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
Breast Satisfaction	Number Analyzed	378 participants	369 participants
		-1.7 (1.2)	1.0 (1.3)
Endocrine Sexual Symptoms	Number Analyzed	428 participants	419 participants
		4.8 (0.8)	2.3 (0.8)
Endocrine Therapy Symptoms	Number Analyzed	437 participants	434 participants
		1.5 (0.6)	1.2 (0.6)
Skin Mucosis Symptoms	Number Analyzed	438 participants	434 participants
		3.5 (0.5)	2.5 (0.5)

13. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks])

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:	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 and were followed until disease progression, death or study cut-off date, whichever comes first (maximum exposure duration: 112 weeks).	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 Number of Participants Analyzed	492	489
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	3.2 (0.5)	3.8 (0.5)

14. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, overall treatment duration (Cycle 1 up to Cycle 21 [i.e., 81 weeks])

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:	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).	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 Number of Participants Analyzed	492	489
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	0.0 (0.0)	0.0 (0.0)

15. Secondary Outcome

Title	Time to First Chemotherapy
Description	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.
Time Frame	From randomization to the start date of the first chemotherapy (maximum duration: 81 weeks)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the ITT population.

Arm/Group Title	Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:	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).	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 Number of Participants Analyzed	534	534
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Median, upper limit and lower limit of 95% CI was not estimable due to lower number of participants with events.

16. Secondary Outcome

Title	Number of Participants With Hematological Abnormalities During the Treatment Period
Description	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.
Time Frame	From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: 112 weeks)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:		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).	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 Number of Participants Analyzed		533	533
Measure Type: Count of Participants; Unit of Measure: Participants
Anemia: Grade 1	Number Analyzed	533 participants	532 participants
		309 58.0%	302 56.8%
Anemia: Grade 2	Number Analyzed	533 participants	532 participants
		108 20.3%	78 14.7%
Anemia: Grade 3	Number Analyzed	533 participants	532 participants
		22 4.1%	17 3.2%
Anemia: Grade 4	Number Analyzed	533 participants	532 participants
		0 0.0%	0 0.0%
Lymphocyte count decreased: Grade 1	Number Analyzed	533 participants	532 participants
		98 18.4%	101 19.0%
Lymphocyte count decreased: Grade 2	Number Analyzed	533 participants	532 participants
		138 25.9%	124 23.3%
Lymphocyte count decreased: Grade 3	Number Analyzed	533 participants	532 participants
		46 8.6%	48 9.0%
Lymphocyte count decreased: Grade 4	Number Analyzed	533 participants	532 participants
		23 4.3%	22 4.1%
Neutrophil count decreased: Grade 1	Number Analyzed	533 participants	532 participants
		22 4.1%	45 8.5%
Neutrophil count decreased: Grade 2	Number Analyzed	533 participants	532 participants
		150 28.1%	217 40.8%
Neutrophil count decreased: Grade 3	Number Analyzed	533 participants	532 participants
		277 52.0%	199 37.4%
Neutrophil count decreased: Grade 4	Number Analyzed	533 participants	532 participants
		70 13.1%	21 3.9%
White blood cell decreased: Grade 1	Number Analyzed	532 participants	531 participants
		81 15.2%	146 27.5%
White blood cell decreased: Grade 2	Number Analyzed	532 participants	531 participants
		279 52.4%	267 50.3%
White blood cell decreased: Grade 3	Number Analyzed	532 participants	531 participants
		163 30.6%	95 17.9%
White blood cell decreased: Grade 4	Number Analyzed	532 participants	531 participants
		7 1.3%	3 0.6%
Platelet count decreased: Grade 1	Number Analyzed	533 participants	532 participants
		285 53.5%	220 41.4%
Platelet count decreased: Grade 2	Number Analyzed	533 participants	532 participants
		30 5.6%	12 2.3%
Platelet count decreased: Grade 3	Number Analyzed	533 participants	532 participants
		18 3.4%	8 1.5%
Platelet count decreased: Grade 4	Number Analyzed	533 participants	532 participants
		8 1.5%	10 1.9%

17. Secondary Outcome

Title	Number of Participants With Liver Function Abnormalities of Grade 3 and 4 During the Treatment Period
Description	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.
Time Frame	From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: 112 weeks)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Letrozole + Palbociclib	Amcenestrant + Palbociclib
Arm/Group Description:		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).	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 Number of Participants Analyzed		533	533
Measure Type: Count of Participants; Unit of Measure: Participants
Aspartate aminotransferase increased: Grade 3	Number Analyzed	533 participants	532 participants
		9 1.7%	23 4.3%
Aspartate aminotransferase increased: Grade 4	Number Analyzed	533 participants	532 participants
		0 0.0%	1 0.2%
Alanine aminotransferase increased: Grade 3	Number Analyzed	533 participants	532 participants
		12 2.3%	32 6.0%
Alanine aminotransferase increased: Grade 4	Number Analyzed	533 participants	532 participants
		1 0.2%	3 0.6%
Alkaline phosphatase increased: Grade 3	Number Analyzed	532 participants	532 participants
		3 0.6%	1 0.2%
Alkaline phosphatase increased: Grade 4	Number Analyzed	532 participants	532 participants
		0 0.0%	0 0.0%
Total bilirubin increased: Grade 3	Number Analyzed	533 participants	532 participants
		3 0.6%	5 0.9%
Total bilirubin increased: Grade 4	Number Analyzed	533 participants	532 participants
		0 0.0%	0 0.0%
Gamma-GT increased: Grade 3	Number Analyzed	533 participants	532 participants
		9 1.7%	20 3.8%
Gamma-GT increased: Grade 4	Number Analyzed	533 participants	532 participants
		0 0.0%	1 0.2%

Adverse Events

Time Frame	Adverse Events (AE) data was collected from Baseline up to 30 days after last dose of study treatment (maximum exposure: 112 weeks), deaths were collected from Baseline up to the end of study (26 May 2023)
Adverse Event Reporting Description	Reported SAEs and NSAEs were assessed for safety population. All-Cause Mortality data collected during study was assessed for all randomized participants. Disease progression related death were not reported as AE.
Arm/Group Title	Letrozole + Palbociclib		Amcenestrant + Palbociclib
Arm/Group Description	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).		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).
All-Cause Mortality
	Letrozole + Palbociclib		Amcenestrant + Palbociclib
	Affected / at Risk (%)		Affected / at Risk (%)
Total	41/534 (7.68%)		45/534 (8.43%)
Serious Adverse Events
	Letrozole + Palbociclib		Amcenestrant + Palbociclib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	68/533 (12.76%)		77/533 (14.45%)
Blood and lymphatic system disorders
Anaemia † 1	4/533 (0.75%)	5	1/533 (0.19%)	1
Anaemia Of Malignant Disease † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Febrile Neutropenia † 1	2/533 (0.38%)	2	2/533 (0.38%)	2
Cardiac disorders
Acute Left Ventricular Failure † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Acute Myocardial Infarction † 1	1/533 (0.19%)	1	2/533 (0.38%)	2
Atrioventricular Block Complete † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Cardiac Failure † 1	2/533 (0.38%)	2	0/533 (0.00%)	0
Heart Valve Incompetence † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Myocardial Infarction † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Gastrointestinal disorders
Abdominal Distension † 1	2/533 (0.38%)	2	0/533 (0.00%)	0
Abdominal Pain † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Abdominal Pain Lower † 1	1/533 (0.19%)	1	1/533 (0.19%)	1
Colitis † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Gastrointestinal Haemorrhage † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Haematemesis † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Intestinal Obstruction † 1	2/533 (0.38%)	2	1/533 (0.19%)	1
Lower Gastrointestinal Haemorrhage † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Nausea † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Pancreatitis Acute † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Upper Gastrointestinal Haemorrhage † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Vomiting † 1	3/533 (0.56%)	3	1/533 (0.19%)	1
General disorders
Death † 1	1/533 (0.19%)	1	1/533 (0.19%)	1
Disease Progression † 1	4/533 (0.75%)	4	1/533 (0.19%)	1
Fatigue † 1	1/533 (0.19%)	1	1/533 (0.19%)	1
General Physical Health Deterioration † 1	0/533 (0.00%)	0	1/533 (0.19%)	2
Non-Cardiac Chest Pain † 1	1/533 (0.19%)	1	1/533 (0.19%)	1
Oedema Peripheral † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Pain † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Pyrexia † 1	1/533 (0.19%)	1	3/533 (0.56%)	4
Hepatobiliary disorders
Bile Duct Stone † 1	2/533 (0.38%)	2	0/533 (0.00%)	0
Cholecystitis † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Hepatic Failure † 1	1/533 (0.19%)	1	2/533 (0.38%)	2
Hepatic Function Abnormal † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Hepatorenal Failure † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Hepatotoxicity † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Infections and infestations
Appendicitis † 1	2/533 (0.38%)	2	2/533 (0.38%)	2
Bronchitis † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Bronchitis Bacterial † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Covid-19 † 1	8/533 (1.50%)	8	4/533 (0.75%)	4
Covid-19 Pneumonia † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Cellulitis † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Device Related Infection † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Erysipelas † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Focal Peritonitis † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Gastroenteritis † 1	1/533 (0.19%)	1	1/533 (0.19%)	1
Herpes Zoster † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Neutropenic Sepsis † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Osteomyelitis † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Paracancerous Pneumonia † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Pneumonia † 1	3/533 (0.56%)	3	1/533 (0.19%)	1
Pyelonephritis † 1	1/533 (0.19%)	1	1/533 (0.19%)	1
Sepsis † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Upper Respiratory Tract Infection † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Urinary Tract Infection † 1	3/533 (0.56%)	3	0/533 (0.00%)	0
Urosepsis † 1	1/533 (0.19%)	1	1/533 (0.19%)	1
Injury, poisoning and procedural complications
Alcohol Poisoning † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Femur Fracture † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Foot Fracture † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Gastrointestinal Procedural Complication † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Gastrointestinal Stoma Complication † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Humerus Fracture † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Procedural Pneumothorax † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Subdural Haematoma † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Tibia Fracture † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Investigations
Alanine Aminotransferase Increased † 1	0/533 (0.00%)	0	2/533 (0.38%)	2
Aspartate Aminotransferase Increased † 1	0/533 (0.00%)	0	2/533 (0.38%)	2
Blood Follicle Stimulating Hormone Decreased † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Metabolism and nutrition disorders
Decreased Appetite † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Dehydration † 1	1/533 (0.19%)	1	1/533 (0.19%)	1
Hyperkalaemia † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Hypocalcaemia † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Hypokalaemia † 1	2/533 (0.38%)	2	0/533 (0.00%)	0
Hyponatraemia † 1	1/533 (0.19%)	1	1/533 (0.19%)	1
Musculoskeletal and connective tissue disorders
Axillary Mass † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Back Pain † 1	1/533 (0.19%)	1	1/533 (0.19%)	1
Flank Pain † 1	0/533 (0.00%)	0	2/533 (0.38%)	2
Neck Pain † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Pain In Extremity † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Pathological Fracture † 1	3/533 (0.56%)	3	1/533 (0.19%)	1
Spinal Pain † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma Of Colon † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Cancer Pain † 1	0/533 (0.00%)	0	2/533 (0.38%)	2
Colon Cancer † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Diffuse Large B-Cell Lymphoma † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Gallbladder Cancer † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Metastases To Liver † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Rectal Adenocarcinoma † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Nervous system disorders
Cerebral Infarction † 1	2/533 (0.38%)	2	1/533 (0.19%)	1
Cerebrovascular Accident † 1	1/533 (0.19%)	1	1/533 (0.19%)	1
Ischaemic Stroke † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Paraesthesia † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Psychomotor Hyperactivity † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Syncope † 1	3/533 (0.56%)	3	0/533 (0.00%)	0
Psychiatric disorders
Delirium † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Psychotic Disorder † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Schizophrenia † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Renal and urinary disorders
Acute Kidney Injury † 1	2/533 (0.38%)	2	0/533 (0.00%)	0
Nephrolithiasis † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Pyelocaliectasis † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Reproductive system and breast disorders
Ovarian Cyst † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Respiratory, thoracic and mediastinal disorders
Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Dyspnoea † 1	4/533 (0.75%)	4	2/533 (0.38%)	2
Haemoptysis † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Hydrothorax † 1	1/533 (0.19%)	1	1/533 (0.19%)	1
Interstitial Lung Disease † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Pleural Effusion † 1	1/533 (0.19%)	1	6/533 (1.13%)	6
Pneumonitis † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Pneumothorax † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
Pulmonary Embolism † 1	3/533 (0.56%)	3	7/533 (1.31%)	7
Pulmonary Oedema † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Respiratory Failure † 1	2/533 (0.38%)	2	3/533 (0.56%)	3
Vascular disorders
Deep Vein Thrombosis † 1	2/533 (0.38%)	2	3/533 (0.56%)	3
Hypertension † 1	1/533 (0.19%)	1	0/533 (0.00%)	0
Vena Cava Thrombosis † 1	0/533 (0.00%)	0	1/533 (0.19%)	1
1 Term from vocabulary, MedDRA 26.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Letrozole + Palbociclib		Amcenestrant + Palbociclib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	448/533 (84.05%)		412/533 (77.30%)
Blood and lymphatic system disorders
Neutropenia † 1	201/533 (37.71%)	538	113/533 (21.20%)	231
Gastrointestinal disorders
Abdominal Pain Upper † 1	28/533 (5.25%)	31	24/533 (4.50%)	24
Constipation † 1	68/533 (12.76%)	84	70/533 (13.13%)	76
Diarrhoea † 1	82/533 (15.38%)	115	62/533 (11.63%)	74
Nausea † 1	92/533 (17.26%)	112	84/533 (15.76%)	102
Stomatitis † 1	93/533 (17.45%)	131	64/533 (12.01%)	88
Vomiting † 1	54/533 (10.13%)	64	39/533 (7.32%)	51
General disorders
Asthenia † 1	46/533 (8.63%)	57	45/533 (8.44%)	55
Fatigue † 1	100/533 (18.76%)	107	93/533 (17.45%)	107
Infections and infestations
Covid-19 † 1	53/533 (9.94%)	53	60/533 (11.26%)	60
Urinary Tract Infection † 1	36/533 (6.75%)	49	38/533 (7.13%)	62
Investigations
Alanine Aminotransferase Increased † 1	18/533 (3.38%)	20	39/533 (7.32%)	44
Neutrophil Count Decreased † 1	114/533 (21.39%)	252	67/533 (12.57%)	118
White Blood Cell Count Decreased † 1	33/533 (6.19%)	72	17/533 (3.19%)	20
Metabolism and nutrition disorders
Decreased Appetite † 1	44/533 (8.26%)	51	39/533 (7.32%)	43
Musculoskeletal and connective tissue disorders
Arthralgia † 1	102/533 (19.14%)	128	110/533 (20.64%)	136
Back Pain † 1	50/533 (9.38%)	60	45/533 (8.44%)	50
Myalgia † 1	29/533 (5.44%)	34	27/533 (5.07%)	30
Pain In Extremity † 1	22/533 (4.13%)	24	45/533 (8.44%)	52
Nervous system disorders
Dizziness † 1	34/533 (6.38%)	41	28/533 (5.25%)	34
Headache † 1	65/533 (12.20%)	79	56/533 (10.51%)	73
Psychiatric disorders
Insomnia † 1	39/533 (7.32%)	40	40/533 (7.50%)	46
Respiratory, thoracic and mediastinal disorders
Cough † 1	30/533 (5.63%)	32	30/533 (5.63%)	34
Dyspnoea † 1	32/533 (6.00%)	35	32/533 (6.00%)	36
Skin and subcutaneous tissue disorders
Alopecia † 1	72/533 (13.51%)	72	44/533 (8.26%)	45
Vascular disorders
Hot Flush † 1	82/533 (15.38%)	86	87/533 (16.32%)	90
Hypertension † 1	20/533 (3.75%)	27	31/533 (5.82%)	42
1 Term from vocabulary, MedDRA 26.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

The study was terminated based on the review by an independent data monitoring committee of the prespecified interim analysis of the Phase 3 AMEERA-5 efficacy data.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement
• Phone: 800-633-1610 ext 6#
• EMail: Contact-US@sanofi.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bardia A, Cortes J, Hurvitz SA, Delaloge S, Iwata H, Shao ZM, Kanagavel D, Cohen P, Liu Q, Cartot-Cotton S, Pelekanou V, O'Shaughnessy J. AMEERA-5: a randomized, double-blind phase 3 study of amcenestrant plus palbociclib versus letrozole plus palbociclib for previously untreated ER+/HER2- advanced breast cancer. Ther Adv Med Oncol. 2022 Mar 15;14:17588359221083956. doi: 10.1177/17588359221083956. eCollection 2022.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT04478266
• Other Study ID Numbers: EFC15935; 2020-001824-33 ( EudraCT Number ); U1111-1233-0486 ( Other Identifier: UTN )
• First Submitted: July 10, 2020
• First Posted: July 20, 2020
• Results First Submitted: June 13, 2023
• Results First Posted: July 6, 2023
• Last Update Posted: December 8, 2023