NCT00567190 · OUTCOME

Overall Survival

A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer · Source last updated 2019-12-13

Results reported by the registry submitting party. Population, time horizon, units and missing values must be read together.

Measure: MEDIAN
Unit: Months
Interval / dispersion: 95% Confidence Interval
Time frame: From randomization to death from any cause, up to each respective analysis data cut-off date (see the Description field for the median time on study per treatment arm)

What was measured

Overall survival (OS) was the time from randomization to death from any cause, using Kaplan-Meier methodology. Survival data was collected every 18 weeks during the post-treatment follow-up period until death, loss to follow-up, or withdrawal of consent. Those who were alive, lost to follow up, or withdrew consent were censored at the latest date they participated in the study; those without post-baseline data were censored at 1 day. OS analyses were planned to take place at the primary completion date (First Interim), after 385 deaths (Event-Driven Final), and at the end of study (End-of-Study). A second interim OS analysis was planned due to a formal request from the European Medicines Agency. Median \[range\] time in weeks on study at each OS analysis (Pertuzumab vs. Placebo): First: 77.1 \[0.7-165.3\] vs. 73.1 \[0.4-165.3\]; Second: 117.1 \[0.7-207.9\] vs. 105.9 \[0.4-207.9\]; Event-Driven Final: 189.9 \[0.7-304.1\] vs. 140.5 \[0.4-301.6\]; End-of-Study: 201.8 \[0.7-520.0\] vs. 138.0 \[0.4-514.7\].

Analysis population: ITT Population: All randomized participants

Groups in this outcome

Pertuzumab + Trastuzumab + Docetaxel

Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m\^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.

Placebo + Trastuzumab + Docetaxel

Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m\^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.

Group identifiers and denominators belong to this outcome only. They may differ in another outcome or in safety reporting.

Analysis denominator · Participants

Group	Source count
Pertuzumab + Trastuzumab + Docetaxel	402
Placebo + Trastuzumab + Docetaxel	406

Reported measurements

End-of-Study OS Analysis

Values in Months · Interval/dispersion: 95% Confidence Interval
Group	Value	Spread	Lower	Upper	Comment
Pertuzumab + Trastuzumab + Docetaxel	57.1	Not reported	50	72	Not reported
Placebo + Trastuzumab + Docetaxel	40.8	Not reported	36	48	Not reported

Event-Driven Final OS Analysis

Values in Months · Interval/dispersion: 95% Confidence Interval
Group	Value	Spread	Lower	Upper	Comment
Pertuzumab + Trastuzumab + Docetaxel	56.5	Not reported	49	NA	The upper limit of the 95% CI could not be determined because it was larger than the maximum follow-up time at data cutoff for the analysis.
Placebo + Trastuzumab + Docetaxel	40.8	Not reported	36	48	Not reported

Second Interim OS Analysis

Values in Months · Interval/dispersion: 95% Confidence Interval
Group	Value	Spread	Lower	Upper	Comment
Pertuzumab + Trastuzumab + Docetaxel	NA	Not reported	42	NA	The median and upper limit of the 95% CI could not be determined because they were larger than the maximum follow-up time at data cutoff for the analysis.
Placebo + Trastuzumab + Docetaxel	37.6	Not reported	34	NA	The upper limit of the 95% CI could not be determined because it was larger than the maximum follow-up time at data cutoff for the analysis.

First Interim OS Analysis

Values in Months · Interval/dispersion: 95% Confidence Interval
Group	Value	Spread	Lower	Upper	Comment
Pertuzumab + Trastuzumab + Docetaxel	NA	Not reported	NA	NA	The median and lower and upper limits of the 95% CI could not be determined because they were larger than the maximum follow-up time at data cutoff for the analysis.
Placebo + Trastuzumab + Docetaxel	NA	Not reported	30	NA	The median and upper limit of the 95% CI could not be determined because they were larger than the maximum follow-up time at data cutoff for the analysis.

Source statistical analyses

Group order, estimate direction, methods and comments are retained. No treatment ranking is inferred.

ci Lower Limit
0.58
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
0.82
estimate Comment
Hazard ratio is comparing Pertuzumab arm with Placebo arm.
group Description
End-of-Study OS Analysis: This end-of-study OS analysis is considered exploratory only as the confirmatory OS analysis for statistical interpretation had previously occurred at the second interim OS analysis.
group Ids
OG000
OG001
non Inferiority Comment
Exploratory
non Inferiority Type
SUPERIORITY
p Value
<0.0001
p Value Comment
Exploratory
param Type
Cox Proportional Hazard
param Value
0.69
statistical Comment
Stratified by prior treatment status and region.
statistical Method
Log Rank (stratified)
ci Lower Limit
0.56
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
0.84
estimate Comment
Hazard ratio is comparing Pertuzumab arm with Placebo arm.
group Description
Event-Driven Final OS Analysis: This final OS analysis was event-driven and planned to take place after a total of 385 deaths had occurred. It is considered exploratory only as the confirmatory OS analysis for statistical interpretation had previously occurred at the second interim OS analysis.
group Ids
OG000
OG001
non Inferiority Comment
Exploratory
non Inferiority Type
SUPERIORITY
p Value
0.0002
p Value Comment
Exploratory
param Type
Cox Proportional Hazard
param Value
0.68
statistical Comment
Stratified by prior treatment status and region.
statistical Method
Log Rank (stratified)
ci Lower Limit
0.52
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
0.84
estimate Comment
Hazard ratio (HR) is comparing Pertuzumab arm with Placebo arm.
group Description
Second Interim OS Analysis: For this second interim OS analysis, the pre-defined O'Brien-Fleming stopping boundary for the Lan-DeMets α-spending function was: HR≤0.739, p≤0.0138.
group Ids
OG000
OG001
non Inferiority Type
SUPERIORITY
p Value
0.0008
p Value Comment
The threshold for statistical significance was HR≤0.739, p≤0.0138.
param Type
Cox Proportional Hazard
param Value
0.66
statistical Comment
Stratified by prior treatment status and region.
statistical Method
Log Rank (stratified)
ci Lower Limit
0.47
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
0.88
estimate Comment
Hazard ratio (HR) is comparing pertuzumab with placebo arms.
group Description
First Interim OS Analysis: For this first interim OS analysis, the pre-defined O'Brien-Fleming stopping boundary for the Lan-DeMets α-spending function was: HR≤0.603, p≤0.0012.
group Ids
OG000
OG001
non Inferiority Type
SUPERIORITY
p Value
0.0050
p Value Comment
The threshold for statistical significance was HR≤0.603, p≤0.0012.
param Type
Cox Proportional Hazard
param Value
0.64
statistical Comment
Stratified by prior treatment status and region.
statistical Method
Log Rank (stratified)

Complete source fields

analyses

ci Lower Limit
0.58
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
0.82
estimate Comment
Hazard ratio is comparing Pertuzumab arm with Placebo arm.
group Description
End-of-Study OS Analysis: This end-of-study OS analysis is considered exploratory only as the confirmatory OS analysis for statistical interpretation had previously occurred at the second interim OS analysis.
group Ids
OG000
OG001
non Inferiority Comment
Exploratory
non Inferiority Type
SUPERIORITY
p Value
<0.0001
p Value Comment
Exploratory
param Type
Cox Proportional Hazard
param Value
0.69
statistical Comment
Stratified by prior treatment status and region.
statistical Method
Log Rank (stratified)
ci Lower Limit
0.56
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
0.84
estimate Comment
Hazard ratio is comparing Pertuzumab arm with Placebo arm.
group Description
Event-Driven Final OS Analysis: This final OS analysis was event-driven and planned to take place after a total of 385 deaths had occurred. It is considered exploratory only as the confirmatory OS analysis for statistical interpretation had previously occurred at the second interim OS analysis.
group Ids
OG000
OG001
non Inferiority Comment
Exploratory
non Inferiority Type
SUPERIORITY
p Value
0.0002
p Value Comment
Exploratory
param Type
Cox Proportional Hazard
param Value
0.68
statistical Comment
Stratified by prior treatment status and region.
statistical Method
Log Rank (stratified)
ci Lower Limit
0.52
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
0.84
estimate Comment
Hazard ratio (HR) is comparing Pertuzumab arm with Placebo arm.
group Description
Second Interim OS Analysis: For this second interim OS analysis, the pre-defined O'Brien-Fleming stopping boundary for the Lan-DeMets α-spending function was: HR≤0.739, p≤0.0138.
group Ids
OG000
OG001
non Inferiority Type
SUPERIORITY
p Value
0.0008
p Value Comment
The threshold for statistical significance was HR≤0.739, p≤0.0138.
param Type
Cox Proportional Hazard
param Value
0.66
statistical Comment
Stratified by prior treatment status and region.
statistical Method
Log Rank (stratified)
ci Lower Limit
0.47
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
0.88
estimate Comment
Hazard ratio (HR) is comparing pertuzumab with placebo arms.
group Description
First Interim OS Analysis: For this first interim OS analysis, the pre-defined O'Brien-Fleming stopping boundary for the Lan-DeMets α-spending function was: HR≤0.603, p≤0.0012.
group Ids
OG000
OG001
non Inferiority Type
SUPERIORITY
p Value
0.0050
p Value Comment
The threshold for statistical significance was HR≤0.603, p≤0.0012.
param Type
Cox Proportional Hazard
param Value
0.64
statistical Comment
Stratified by prior treatment status and region.
statistical Method
Log Rank (stratified)

classes

categories
measurements
group Id
OG000
lower Limit
50
upper Limit
72
value
57.1
group Id
OG001
lower Limit
36
upper Limit
48
value
40.8
title
End-of-Study OS Analysis
categories
measurements
comment
The upper limit of the 95% CI could not be determined because it was larger than the maximum follow-up time at data cutoff for the analysis.
group Id
OG000
lower Limit
49
upper Limit
NA
value
56.5
group Id
OG001
lower Limit
36
upper Limit
48
value
40.8
title
Event-Driven Final OS Analysis
categories
measurements
comment
The median and upper limit of the 95% CI could not be determined because they were larger than the maximum follow-up time at data cutoff for the analysis.
group Id
OG000
lower Limit
42
upper Limit
NA
value
NA
comment
The upper limit of the 95% CI could not be determined because it was larger than the maximum follow-up time at data cutoff for the analysis.
group Id
OG001
lower Limit
34
upper Limit
NA
value
37.6
title
Second Interim OS Analysis
categories
measurements
comment
The median and lower and upper limits of the 95% CI could not be determined because they were larger than the maximum follow-up time at data cutoff for the analysis.
group Id
OG000
lower Limit
NA
upper Limit
NA
value
NA
comment
The median and upper limit of the 95% CI could not be determined because they were larger than the maximum follow-up time at data cutoff for the analysis.
group Id
OG001
lower Limit
30
upper Limit
NA
value
NA
title
First Interim OS Analysis

denoms

counts
group Id
OG000
value
402
group Id
OG001
value
406
units
Participants

description

dispersion Type

95% Confidence Interval

groups

description
Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m\^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
id
OG000
title
Pertuzumab + Trastuzumab + Docetaxel
description
Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m\^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
id
OG001
title
Placebo + Trastuzumab + Docetaxel

param Type

MEDIAN

population Description

ITT Population: All randomized participants

reporting Status

POSTED

time Frame

From randomization to death from any cause, up to each respective analysis data cut-off date (see the Description field for the median time on study per treatment arm)

title

Overall Survival

type

SECONDARY

unit Of Measure

Months

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