A Study Of Palbociclib (PD-0332991) + Letrozole VS. Placebo+ Letrozole For 1st Line Treatment Of Asian Postmenopausal Women With ER+/HER2- Advanced Breast Cancer [PALOMA-4]

PFS was based on Kaplan-Meier estimates. PFS was defined as the time from the date of randomization to the date of the first documentation of objective progression of disease (PD) or death due to any cause in the absence of documented PD, whichever occurred first. PD is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) as a 20% increase in the sum of 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. In this outcome measure, PFS was based on investigator's assessment.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population, including all participants who were randomized, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

OS was defined as the time from date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. The 1-year survival probability was estimated using the Kaplan-Meier method and a 2-sided 95% confidence interval (CI) for the log \[-log(1 year survival probability)\] was be calculated using a normal approximation, and then back transformed to give a CI for the 1-year survival probability itself. The 2-year, and 3-year survival probabilities were estimated similarly.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population, including all participants who were randomized, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

DOR was defined as the time from the first documentation of objective tumor response (complete response \[CR\] or partial response \[PR\]) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. DOR data was censored on the date of the last tumor assessment on study for participants who did not have objective tumor progression and who did not die due to any cause while on study. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis \<10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. In this outcome measure, DOR was based on BICR.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population with objective disease response, including all participants who were randomized, with objective disease response and study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

DOR was defined as the time from the first documentation of objective tumor response (complete response \[CR\] or partial response \[PR\]) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. DOR data was censored on the date of the last tumor assessment on study for participants who did not have objective tumor progression and who did not die due to any cause while on study. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis \<10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. In this outcome measure, DOR was based on investigator assessment.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population with objective disease response, including all participants who were randomized, with objective disease response and study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

Archived formalin-fixed paraffin embedded (FFPE) specimen from the original diagnostic tumor tissue was collected and sent to the sponsor-designated central laboratories for assessment of Ki67 associated with sensitivity and/or resistance to Palbociclib.

Time frame: Baseline

Population: This was a subset of as-treated (AT) population (participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received), who had both baseline and at least 1 follow-up values for Ki67.

The EQ-5D is a 6-item instrument designed to assess health status in terms of a single index value or utility score. It consists of 5 descriptors of current health state (mobility, self care, usual activities, pain/discomfort, and anxiety/depression); a participant was asked to rate each state on a 3 level scale (1=no problem, 2=some problem, and 3=extreme problem) with higher levels indicating greater severity/impairment.

Time frame: Baseline up to Cycle 65 Day 1

Population: This was a subset of intent-to-treat (ITT) population (participants who were randomized, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized), who had both baseline and who completed all 5 items needed to calculated the index-based summary score ata the respective cycle.

The EQ VAS recorded the participant's self rated questionnaire to assess generic health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state). Published weights were available that allow for the creation of a single summary score.

Time frame: Baseline up to Cycle 65 Day 1

Population: This was a subset of intent-to-treat (ITT) population (participants who were randomized, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized), who had both baseline and who completed all 5 items needed to calculated the index-based summary score ata the respective cycle.

The Functional Assessment of Cancer Therapy (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 was 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 consists of the FACT-G (27 items) 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 5-level scale ranging from 0=Not at all to 4=Very much. FACT-B total score = FACT-G + Breast Cancer Subscale. As each of the items ranges from 0-4, the range of possible scores is 0-148, with 0 being the worst possible score and 148 the best. A positive change of the total score indicated improvement from baseline and a negative change indicated deterioration.

Time frame: Baseline up to Cycle 65 Day 1

Population: This was a subset of intent-to-treat (ITT) population (participants who were randomized, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized), who had both baseline and who completed \>80% of the corresponding questions and had valid scores for the relevant subscales.

Archived formalin-fixed paraffin embedded (FFPE) specimen from the original diagnostic tumor tissue was collected and sent to the sponsor-designated central laboratories for assessment of ER associated with sensitivity and/or resistance to Palbociclib.

Time frame: Baseline

Population: This was a subset of as-treated (AT) population (participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received), who had both baseline and at least 1 follow-up values for ER.

The laboratory results were graded according to the National Cancer Institute (NCI) CTCAE v4.0 severity grade. Shift tables were provided to examine the distribution of laboratory toxicities. The following chemistry parameters had met the criteria of CTCAE grade shift change from Grade \<=2 at baseline to Grade 3 or 4 post baseline: alanine aminotransferase (ALT), alkaline phosphatase, aspartate aminotransferase (AST), bilirubin (total), creatinine, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, and hyponatremia.

Time frame: Randomization up to 65 months

Population: This was as-treated (AT) population, including all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

The laboratory results were graded according to the National Cancer Institute (NCI) CTCAE v4.0 severity grade. Shift tables were provided to examine the distribution of laboratory toxicities. The following hematology parameters had met the criteria of CTCAE grade shift change from Grade \<=2 at baseline to Grade 3 or 4 post baseline: neutrophils (absolute), white blood cells, platelets, anemia and hemoglobin increased.

Time frame: Randomization up to 65 months

Population: This was as-treated (AT) population, including all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events 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. Participants were counted only once per treatment in each row.

Time frame: Randomization up to 65 months

Population: This was as-treated (AT) population, including all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events 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. Relatedness to treatment was assessed by the investigator (Yes/No). Participants were counted only once per treatment in each row.

Time frame: Randomization up to 65 months

Population: This was as-treated (AT) population, including all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

OS was defined as the time from date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. OS was assessed using Kaplan-Meier methods.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population, including all participants who were randomized, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

OR was defined as a complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 recorded from randomization until disease progression or death due to any cause. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis \<10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. In this outcome measure, OR was based on investigator assessment.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population, including all participants who were randomized, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

DC/CBR was defined as CR, PR, or stable disease (SD) \>=24 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) recorded in the time period between randomization and disease progression or death to any cause. CR was defined as complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size (short axis \<10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. SD was defined as not qualifying for CR, PR, PD. PD is defined using RECIST v1.1 as a 20% increase in the sum of of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm. In this outcome measure, DC/CBR was based on BICR.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population, including all participants who were randomized, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

DC/CBR was defined as CR, PR, or stable disease (SD) \>=24 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) recorded in the time period between randomization and disease progression or death to any cause. CR was defined as complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size (short axis \<10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. SD was defined as not qualifying for CR, PR, PD. PD is defined using RECIST v1.1 as a 20% increase in the sum of of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm. In this outcome measure, DC/CBR was based on BICR.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population with measureable disease at baseline, including the participants, who were randomized, with measureable disease at baseline, and study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

DC/CBR was defined as CR, PR, or stable disease (SD) \>=24 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) recorded in the time period between randomization and disease progression or death to any cause. CR was defined as complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size (short axis \<10 mm). No new lesions. The PR was defined as \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. SD was defined as not qualifying for CR, PR, PD. PD is defined using RECIST v1.1 as a 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm. In this outcome measure, DC/CBR was based on investigator assessment.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population, including all participants who were randomized, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

DC/CBR was defined as CR, PR, or stable disease (SD) \>=24 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) recorded in the time period between randomization and disease progression or death to any cause. CR was defined as complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size (short axis \<10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. SD was defined as not qualifying for CR, PR, PD. PD is defined using RECIST v1.1 as a 20% increase in the sum of of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm. In this outcome measure, DC/CBR was based on investigator assessment.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population with measureable disease at baseline, including the participants, who were randomized, with measureable disease at baseline, and study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

OR was defined as a complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 recorded from randomization until disease progression or death due to any cause. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis \<10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. In this outcome measure, OR was based on BICR.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population, including all participants who were randomized, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

OR was defined as a complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 recorded from randomization until disease progression or death due to any cause. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis \<10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. In this outcome measure, OR was based on BICR.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population with measureable disease at baseline, including the participants, who were randomized, with measureable disease at baseline, and study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

OR was defined as a complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 recorded from randomization until disease progression or death due to any cause. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis \<10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. In this outcome measure, OR was based on investigator assessment.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population with measureable disease at baseline, including the participants, who were randomized, with measureable disease at baseline, and study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

PFS was based on Kaplan-Meier estimates. PFS was defined as time from the first dose of study treatment to the first documentation of objective tumor progression or to death due to any cause in the absence of documented progressive disease, whichever occurs first. In this outcome measure, PFS was based on BICR.

Time frame: Randomization up to 65 months

Population: This was intent-to-treat (ITT) population, including all participants who were randomized, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

Summary of palbociclib trough concentrations

Time frame: Pre-dose on Day 14 of Cycle 1 and Cycle 2

Population: This was a subset of as-treated (AT) population (participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received), including all participants who are treated with palbociclib and have at least 1 measured plasma concentration.