Trial Outcomes & Findings for A Study of Palbociclib (PD-0332991) + Letrozole vs. Letrozole For 1st Line Treatment Of Postmenopausal Women With ER+/HER2- Advanced Breast Cancer (PALOMA-2) (NCT NCT01740427)

Last Updated: 2024-11-14

Results Overview

PFS is defined as the time from the date of randomization to the date of the first documentation of objective tumor progression as per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) or death due to any cause in the absence of documented PD, whichever occurs first. If tumor progression data include more than 1 date, the first date will be used. PFS (in months) will be calculated as (first event date - randomization date +1)/30.4. Progression is defined using RECIST v1.1, as a 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm, or unequivocal progression of pre-existing non-target lesions, or the appearance of new lesions.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

666 participants

Primary outcome timeframe

From randomization date to date of first documentation of progression or death (up to approximately 2.5 years)

Results posted on

2024-11-14

Participant Flow

A total of 666 participants were randomized at 239 centers in 19 countries.

The study consisted of a screening visit within 28 days before randomization, an active treatment phase, divided in cycles of 28 days each, and a post-treatment follow-up period during which survival and new anti-cancer therapy information was collected every 6 months (±7 days) from the last dose of study treatment.

Participant milestones

Participant milestones
Measure	Palbociclib Plus Letrozole Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Overall Study STARTED	444	222
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	444	222

Reasons for withdrawal

Reasons for withdrawal
Measure	Palbociclib Plus Letrozole Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Overall Study Objective Progression or Relapse	286	172
Overall Study Adverse Event	32	9
Overall Study Global Deterioration of Health Status	28	12
Overall Study Participant Refused Continued Treatment	27	15
Overall Study Unspecified reasons	52	8
Overall Study Death	10	3
Overall Study Protocol Violation	5	3
Overall Study Lost to Follow-up	3	0
Overall Study Site Terminated by Sponsor	1	0

Baseline Characteristics

A Study of Palbociclib (PD-0332991) + Letrozole vs. Letrozole For 1st Line Treatment Of Postmenopausal Women With ER+/HER2- Advanced Breast Cancer (PALOMA-2)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Palbociclib Plus Letrozole n=444 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=222 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Total n=666 Participants Total of all reporting groups
Age, Continuous	61.7 Years STANDARD_DEVIATION 10.6 • n=5 Participants	60.6 Years STANDARD_DEVIATION 11.2 • n=7 Participants	61.3 Years STANDARD_DEVIATION 10.8 • n=5 Participants
Sex: Female, Male Female	444 Participants n=5 Participants	222 Participants n=7 Participants	666 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization date to date of first documentation of progression or death (up to approximately 2.5 years)

Population: ITT population or full analysis set included all participants who were randomized, with study drug assignment designated according to initial randomization, regardless of whether participants received study medication or received a different drug from that to which they were randomized.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=444 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=222 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Progression-Free Survival (PFS) as Assessed by the Investigator	24.8 Months Interval 22.1 to The value was not available because there was not enough disease progression events in the treatment group at the time of analysis, due to drug benefit.	14.5 Months Interval 12.9 to 17.1

SECONDARY outcome

Timeframe: From randomization until end of treatment (up to approximately 2.5 years)

Population: ITT population or full analysis set included all participants who were randomized, with study medication, regardless of whether participants received study medication or received a different drug from that to which they were randomized.

Objective Response (OR) defined as overall complete response (CR) or partial response (PR) according to RECIST v1.1. Objective Response Rate (ORR) is defined as proportion of participants with CR or PR relative to all randomized participants with measurable disease at baseline. Participants who do not have on-study radiographic tumor re-evaluation, who received anti-tumor treatment, or who died, progressed/ dropped out for any reason prior to reaching a CR or PR were counted as non-responders in assessment of ORR. Per RECIST v1.1, CR: Complete disappearance of target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis \<10mm). PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter is used in the sum for target nodes, while the longest diameter is used in the sum for all other target lesions. Stable Disease: neither sufficient shrinkage nor increase to qualify for disease progression.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=444 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=222 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Objective Response as Assessed by the Investigator	46.4 Percentage of participants Interval 41.7 to 51.2	38.3 Percentage of participants Interval 31.9 to 45.0

SECONDARY outcome

Timeframe: From randomization until end of treatment (up to approximately 2.5 years)

Population: Participants who had measurable disease at baseline.

The OR is defined as the overall CR or PR according to the RECIST v1.1. ORR is defined as proportion of participants with CR or PR relative to all randomized participants with measurable disease at baseline. Participants who do not have on-study radiographic tumor re-evaluation, who received anti-tumor treatment, or who died, progressed/ dropped out for any reason prior to reaching a CR or PR were counted as non-responders in the assessment of ORR. Per RECIST v1.1, CR: Complete disappearance of target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis \<10mm). PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter is used in the sum for target nodes, while the longest diameter is used in the sum for all other target lesions. Stable Disease: neither sufficient shrinkage nor increase to qualify for disease progression.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=338 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=171 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Objective Response: Participants With Measurable Disease at Baseline as Assessed by the Investigator	60.7 Percentage of participants Interval 55.2 to 65.9	49.1 Percentage of participants Interval 41.4 to 56.9

SECONDARY outcome

Timeframe: From randomization until end of treatment (up to approximately 2.5 years)

Population: Participants who had tumor response with CR or PR during study.

DR is defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurs first. If tumor progression data included more than 1 date, the first date will be used. DR was calculated as \[the date response ended (i.e. date of PD or death) - first CR or PR date + 1)\]/30.4. DR would only be calculated for the subgroup of participants with an objective tumor response. Per RECIST v1.1, CR: Complete disappearance of target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis \<10mm). PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions.The short diameter is used in the sum for target nodes, while the longest diameter is used in the sum for all other target lesions. Stable Disease: neither sufficient shrinkage nor increase to qualify for disease progression.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=206 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=85 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Duration of Response (DR)	20.1 Months Interval 19.3 to 28.0	16.7 Months Interval 13.8 to 22.5

SECONDARY outcome

Timeframe: From randomization until end of treatment (up to approximately 2.5 years)

DC is defined as overall CR, PR, or stable disease (SD) \>=24 weeks according to RECIST version 1.1. Disease Control Rate (DCR) is defined as participants with CR, PR, or SD \>=24 weeks relative to all randomized participants. Participants who do not have on-study radiographic tumor reevaluation, who received anti-tumor treatment, a best response of SD\>=24 weeks, or who died, progressed, or dropped out for any reason prior to achieving reaching a CR or PR and a best response of SD\>=24 weeks was counted as non-responders in DCR. Per RECIST v1.1, CR: Complete disappearance of target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis \<10mm). PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter is used in the sum for target nodes, while the longest diameter is used in the sum for all other target lesions. SD: neither sufficient shrinkage nor increase to qualify for disease progression.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=444 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=222 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Disease Control (DC)/Clinical Benefit Response (CBR)	85.8 Percentage of participants Interval 82.2 to 88.9	71.2 Percentage of participants Interval 64.7 to 77.0

SECONDARY outcome

Timeframe: From randomization until end of treatment (up to approximately 24 Months)

PFS by biomarker status by Investigator assessment. Progression is defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Positive is defined as H-Score \>=1 and negative as H-Score \<1. H-Score is calculated as the sum of the % of cells at each level of staining intensity (0, 1+, 2+, and 3+) multiplied by the staining intensity value: H-Score = (% at 0)\*0 + (% at 1+)\*1 + (% at 2+)\*2 + (% at 3+)\*3. H-Score values range from 0 to 300. ER stands for estrogen receptor and Rb stands for retinoblastoma susceptibility gene product.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=444 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=222 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
PFS by Tumor Tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6) ER Positive	24.9 Months Interval 22.2 to Not reached; insufficient number of participants with events.	16.3 Months Interval 12.9 to 19.1
PFS by Tumor Tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6) ER Negative	15.6 Months Interval 8.3 to 22.0	5.4 Months Interval 2.7 to 11.1
PFS by Tumor Tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6) Rb Positive	24.2 Months Interval 21.4 to 25.7	13.7 Months Interval 11.0 to 16.5
PFS by Tumor Tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6) Rb Negative	NA Months Interval 11.4 to Not reached; insufficient number of participants with events.	18.5 Months Interval 2.9 to Not reached; insufficient number of participants with events.
PFS by Tumor Tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6) Cyclin D1 Positive	24.8 Months Interval 21.5 to 27.6	13.8 Months Interval 11.3 to 16.8
PFS by Tumor Tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6) Cyclin D1 Negative	11.1 Months Interval 2.2 to 23.9	8.1 Months Interval 0.4 to Not reached; insufficient number of participants with events.
PFS by Tumor Tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6) p16 Positive	24.8 Months Interval 21.5 to Not reached; insufficient number of participants with events.	13.8 Months Interval 11.1 to 16.8
PFS by Tumor Tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6) p16 Negative	16.8 Months Interval 11.1 to 24.9	13.8 Months Interval 8.1 to Not reached; insufficient number of participants with events.
PFS by Tumor Tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6) p16 H-Score<175	23.7 Months Interval 19.6 to 25.7	13.8 Months Interval 11.2 to 16.8
PFS by Tumor Tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6) p16 H-Score>=175	24.2 Months Interval 11.1 to Not reached; insufficient number of participants with events.	5.6 Months Interval 1.5 to 19.1
PFS by Tumor Tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6) Ki67 <=20%	27.6 Months Interval 24.2 to Not reached; insufficient number of participants with events.	16.8 Months Interval 13.7 to 22.0
PFS by Tumor Tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6) Ki67 >20%	17.5 Months Interval 13.8 to 22.0	8.4 Months Interval 5.6 to 13.6

SECONDARY outcome

Timeframe: Time-matched triplicate ECGs were collected at 0 (predose), 2, 4, 6 and 8 hours on Day 0 and on Cycle1 Day14

Population: QTc analysis set is a subset of as treated (AT) population who were in Group 1; their QTc was used to study the effect of palbociclib on QT interval via serial triplicate ECGs with PK draws; and who had \>= 1 pair of time-matched Day 0 and palbociclib postdose (Cycle1 Day14) measurements.

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and sent to a central laboratory for blinded manual adjudication. The average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR), by Bazette's formula (QTcB = QT divided by square root of RR) and corrected QT interval according to study-specific criteria (QTcS). Time-matched change from baseline values were reported for QTc analysis population.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=76 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=47 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcS at 0 hour	0.80 msec Interval -1.67 to 3.26	2.95 msec Interval -0.19 to 6.1
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcS at 2 hour	3.32 msec Interval 0.79 to 5.85	1.65 msec Interval -1.48 to 4.78
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcS at 4 hour	2.76 msec Interval 0.23 to 5.3	1.74 msec Interval -1.39 to 4.87
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcS at 6 hour	4.49 msec Interval 1.96 to 7.02	0.72 msec Interval -2.41 to 3.85
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcS at 8 hour	0.94 msec Interval -1.6 to 3.48	3.14 msec Interval 0.01 to 6.27
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcF at 0 hour	1.10 msec Interval -1.39 to 3.58	3.06 msec Interval -0.11 to 6.23
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcF at 2 hour	3.68 msec Interval 1.12 to 6.23	1.73 msec Interval -1.43 to 4.88
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcF at 4 hour	2.86 msec Interval 0.31 to 5.41	1.54 msec Interval -1.62 to 4.7
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcF at 6 hour	4.57 msec Interval 2.01 to 7.12	0.71 msec Interval -2.44 to 3.87
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcF at 8 hour	1.21 msec Interval -1.36 to 3.77	2.84 msec Interval -0.31 to 6.0
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcB at 0 hour	-0.11 msec Interval -2.83 to 2.61	2.78 msec Interval -0.69 to 6.25
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcB at 2 hour	1.46 msec Interval -1.34 to 4.25	0.83 msec Interval -2.63 to 4.28
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcB at 4 hour	2.58 msec Interval -0.22 to 5.38	2.47 msec Interval -0.98 to 5.92
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcB at 6 hour	4.03 msec Interval 1.24 to 6.83	0.53 msec Interval -2.92 to 3.99
Corrected QT Interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14 QTcB at 8 hour	-0.17 msec Interval -2.98 to 2.64	4.14 msec Interval 0.69 to 7.59

SECONDARY outcome

Timeframe: For safety monitoring triplicate ECGs were obtained at 0 hour (pre-dose) on Day 1 of Cycle 1, Day 14 of Cycles 1 and Cycle 2, then on Day 1 of Cycles 4, 7, and 10 (ECGs beyond Cycle 10 were performed as clinically indicated)

Population: The AT population or safety analysis set included all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and sent to a central laboratory for blinded manual adjudication. The average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR), by Bazette's formula (QTcB = QT divided by square root of RR) and corrected QT interval according to study-specific criteria (QTcS). Percentage of participants with post-baseline maximum absolute values and maximum increase from baseline were summarized for the safety analysis population.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=441 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=220 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcS <450 msec	80.5 Percentage of participants	85.9 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcS 450-<480 msec	17.9 Percentage of participants	11.8 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcS 480-<500 msec	1.1 Percentage of participants	2.3 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcS >=500 msec	0.5 Percentage of participants	0 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcF <450 msec	85.9 Percentage of participants	89.5 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcF 450-<480 msec	12.2 Percentage of participants	9.5 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcF 480-<500 msec	1.6 Percentage of participants	0.9 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcF >=500 msec	0.2 Percentage of participants	0 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcB <450 msec	64.9 Percentage of participants	69.1 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcB 450-<480 msec	32.2 Percentage of participants	27.3 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcB 480-<500 msec	2.3 Percentage of participants	3.2 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcB >=500 msec	0.7 Percentage of participants	0.5 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcS Change <30 msec	92.7 Percentage of participants	94.5 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcS 30<=Change <60 msec	6.6 Percentage of participants	5.5 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcS Change>=60 msec	0.7 Percentage of participants	0 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcF Change <30 msec	91.6 Percentage of participants	93.6 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcF 30<=Change <60 msec	7.9 Percentage of participants	6.4 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcF Change>=60 msec	0.5 Percentage of participants	0 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcB Change <30 msec	88.9 Percentage of participants	91.4 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcB 30<=Change <60 msec	10.2 Percentage of participants	8.2 Percentage of participants
Percentage of Participants With Corrected QT Interval (QTc) Maximum QTcB Change>=60 msec	0.9 Percentage of participants	0.5 Percentage of participants

SECONDARY outcome

Timeframe: 0 hour (predose) on Day 14 of cycles 1 and 2

Population: Pharmacokinetic analysis set was a subset of AT participants, who were treated with Palbociclib and had at least one measured plasma concentration. Here "Number Analyzed" signifies number of participants evaluable for specified rows.

Summary of plasma palbociclib within-participant mean steady-state trough concentrations.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=423 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Observed Plasma Trough Concentration (Ctrough) at Steady-State Cycle 1 Day 14	70.1 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 59	—
Observed Plasma Trough Concentration (Ctrough) at Steady-State Cycle 2 Day 14	64.2 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 82	—

SECONDARY outcome

Timeframe: From Baseline up to 2.5 years

Population: Patient Reported Outcome (PRO) Analysis Set is a subset of ITT participants, who had both baseline and at least one follow-up PRO assessment.

The EuroQol EQ-5D is a 6-item instrument designed to assess health status in terms of a single index value or utility score. It contains 5 descriptors of current health state (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) with each dimension having 3 levels of function (1=no problem, 2=some problem, and 3=extreme problem). The scores on the 5 descriptors are summarized to create a single summary score. An overall utility score is calculated based on these domains, with a range score from 0 (worse health scenario) to a maximum of 1.0 (best health scenario).

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=437 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=218 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Change From Baseline Between Treatment Comparison in Euro Quality of Life (EQ-5D) Index	0.014 Units on a scale Interval 0.0 to 0.03	-0.010 Units on a scale Interval -0.03 to 0.01

SECONDARY outcome

Timeframe: From Baseline up to 2.5 years

Population: Patient Reported Outcome (PRO) Analysis Set is a subset of ITT participants, who had both baseline and at least one follow-up PRO assessment.

FACT is a modular approach to assess participant health-related quality of life using a 'core' set of questions (FACT-G) as well as a cancer site-specific module. The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. The FACT-B consisted of the FACT-G (27-item) and a breast-specific module: a 10-item instrument designed to assess participant concerns relating to breast cancer. For all questions, participants were asked to respond to a five-level scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much. FACT-B total score = Physical Well-Being + Social/Family Well-Being + Emotional Well-Being + Functional Well-Being + Breast Cancer Subscale. As each of the items ranges from 0-4, the range of possible scores is 0-144, with 0 being the worst possible score and 144 the best.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=439 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=218 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Change From Baseline Between Treatment Comparison in Functional Assessment of Cancer Therapy-Breast (FACT-B)	-0.106 Units on a scale Interval -1.42 to 1.21	0.219 Units on a scale Interval -1.68 to 2.12

SECONDARY outcome

Timeframe: From date of randomization up to 28 days after last dose of study drug (final analysis till study completion, approximately up to 10.51 years)

Population: AT population included all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

An AE was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. SAE was any untoward medical occurrence at any dose that resulted in death; was life-threatening; required hospitalization; resulted in persistent or significant disability or in congenital anomaly/birth defect. TEAE were events that occurred between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Severity was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0 as Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening and Grade 5 = death related to AE. Discontinuation included permanent, temporary discontinuation and dose reduction due to AEs.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=444 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=222 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs): All Causalities Participants with AEs	99.1 Percentage of participants	96.4 Percentage of participants
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs): All Causalities Participants with SAEs	28.2 Percentage of participants	17.1 Percentage of participants
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs): All Causalities Participants with Grade 3 or 4 AEs	83.1 Percentage of participants	30.2 Percentage of participants
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs): All Causalities Participants with Grade 5 AEs	3.6 Percentage of participants	2.3 Percentage of participants
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs): All Causalities Permanently discontinued study due to AEs	4.1 Percentage of participants	2.3 Percentage of participants
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs): All Causalities Permanently disc. palbociclib/placebo due to AEs	14.4 Percentage of participants	6.3 Percentage of participants
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs): All Causalities Permanently discontinued letrozole due to AEs	9.2 Percentage of participants	5.9 Percentage of participants
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs): All Causalities Temporarily disc. palbociclib/placebo due to AEs	79.7 Percentage of participants	17.1 Percentage of participants
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs): All Causalities Temporarily discontinued letrozole due to AEs	23.0 Percentage of participants	11.3 Percentage of participants
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs): All Causalities With palbociclib/placebo dose reduction due to AEs	41.9 Percentage of participants	2.3 Percentage of participants

SECONDARY outcome

Timeframe: From date of randomization until death due to any cause or censored, (assessed up to data cut-off date of 15-Nov-2021, approximately 8.7 years)

OS was defined as the time from date of randomization to date of death due to any cause. Participants without survival data beyond the date of their last follow-up were censored on the last date they were known to be alive. Data for this outcome measure was reported at primary analysis.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=444 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=222 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Overall Survival (OS): Primary Analysis	53.9 Months Interval 49.8 to 60.8	51.2 Months Interval 43.7 to 58.9

SECONDARY outcome

Timeframe: From date of randomization until death due to any cause or censored (final analysis till study completion, approximately up to 10.51 years)

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=444 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=222 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Overall Survival (OS): Final Analysis	53.8 Months Interval 49.8 to 59.2	49.8 Months Interval 42.3 to 56.4

SECONDARY outcome

Timeframe: 1, 2 and 3 years after randomization

One, two or three-year survival probability was defined as the probability of survival 1 year, 2 or 3 years after the date of randomization. The survival probability was estimated using the Kaplan-Meier method and 2-sided 95% confidence interval (CI) was calculated using the product limit method.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=444 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=222 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Survival Probability at 1 Year, 2 Year and 3 Year 1 year survival probability	92.7 Percent probability Interval 89.8 to 94.7	94.9 Percent probability Interval 91.0 to 97.2
Survival Probability at 1 Year, 2 Year and 3 Year 2 year survival probability	78.4 Percent probability Interval 74.1 to 82.0	82.5 Percent probability Interval 76.6 to 87.0
Survival Probability at 1 Year, 2 Year and 3 Year 3 year survival probability	69.8 Percent probability Interval 65.1 to 73.9	65.0 Percent probability Interval 58.0 to 71.1

SECONDARY outcome

Timeframe: From randomization up to 28 days after last dose of study drug (assessed up to analysis date of 15-Nov-2021, approximately 8.7 years)

Population: AT population included all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

Laboratory abnormalities included anemia, hemoglobin increased, neutrophils (absolute), platelets, white blood cells, alanine aminotransferase (ALT), alkaline phosphatase, aspartate aminotransferase (AST), bilirubin (total), creatinine, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypokalemia, hypomagnesemia and hyponatremia. Laboratory abnormalities were graded by CTCAE version (v) 4.0 as Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe and Grade 4 = life-threatening. Categories with at least 1 non-zero data values are reported.

Outcome measures

Outcome measures
Measure	Palbociclib Plus Letrozole n=444 Participants Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.	Placebo Plus Letrozole n=221 Participants Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Anemia: Grade 1-2	328 Participants	90 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Anemia: Grade 3	30 Participants	6 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hemoglobin Increased: Grade 1-2	14 Participants	25 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hemoglobin Increased: Grade 3	1 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Neutrophils (Absolute): Grade 1-2	109 Participants	42 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Neutrophils (Absolute): Grade 3	254 Participants	2 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Neutrophils (Absolute): Grade 4	60 Participants	1 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Platelets: Grade 1-2	289 Participants	32 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Platelets: Grade 3	6 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Platelets: Grade 4	1 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade White Blood Cells: Grade 1-2	248 Participants	57 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade White Blood Cells: Grade 3	177 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade White Blood Cells: Grade 4	6 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade ALT: Grade 1-2	222 Participants	76 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade ALT: Grade 3	16 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade ALT: Grade 4	1 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Alkaline Phosphatase: Grade 1-2	174 Participants	95 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Alkaline Phosphatase: Grade 3	7 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade AST: Grade 1-2	260 Participants	82 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade AST: Grade 3	23 Participants	2 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Bilirubin (Total): Grade 1-2	33 Participants	11 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Bilirubin (Total): Grade 3	3 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Creatinine: Grade 1-2	418 Participants	201 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Creatinine: Grade 3	8 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Creatinine: Grade 4	2 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypercalcemia: Grade 1-2	111 Participants	54 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypercalcemia: Grade 3	1 Participants	2 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hyperkalemia: Grade 1-2	118 Participants	51 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hyperkalemia: Grade 3	6 Participants	1 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hyperkalemia: Grade 4	2 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypermagnesemia: Grade 1-2	71 Participants	26 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypermagnesemia: Grade 3	9 Participants	6 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypermagnesemia: Grade 4	2 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypernatremia: Grade 1-2	94 Participants	35 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypernatremia: Grade 3	8 Participants	1 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypoalbuminemia: Grade 1-2	118 Participants	42 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypoalbuminemia: Grade 3	2 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypocalcemia: Grade 1-2	158 Participants	48 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypocalcemia: Grade 3	4 Participants	1 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypocalcemia: Grade 4	3 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypokalemia: Grade 1-2	105 Participants	32 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypokalemia: Grade 3	11 Participants	2 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypomagnesemia: Grade 1-2	127 Participants	41 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypomagnesemia: Grade 3	1 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hypomagnesemia: Grade 4	2 Participants	0 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hyponatremia: Grade 1-2	107 Participants	44 Participants
Number of Participants With Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade Hyponatremia: Grade 3	11 Participants	4 Participants

Adverse Events

Palbociclib Plus Letrozole

Serious events: 125 serious events

Other events: 435 other events

Deaths: 16 deaths

Placebo Plus Letrozole

Serious events: 38 serious events

Other events: 209 other events

Deaths: 6 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER