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A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Participants With Metastatic Breast Cancer (MARIANNE)

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ClinicalTrials.gov Identifier: NCT01120184
Recruitment Status : Completed
First Posted : May 10, 2010
Results First Posted : February 23, 2017
Last Update Posted : November 7, 2017
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Breast Cancer
Interventions Drug: docetaxel
Drug: paclitaxel
Drug: pertuzumab
Drug: pertuzumab-placebo
Drug: trastuzumab [Herceptin]
Drug: trastuzumab emtansine
Enrollment 1095
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy. Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination. Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Period Title: Overall Study
Started 365 367 363
Treated 355 365 360
Completed 0 0 0
Not Completed 365 367 363
Reason Not Completed
Adverse Event             0             1             0
Lost to Follow-up             13             13             11
Physician Decision             9             1             3
Reason not Specified             8             3             12
Sponsor Decision to Terminate Study             133             144             143
Subject/ Guardian Decision to Withdraw             32             29             25
Death             170             176             169
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab Total
Hide Arm/Group Description Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy. Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination. Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination. Total of all reporting groups
Overall Number of Baseline Participants 365 367 363 1095
Hide Baseline Analysis Population Description
Intent-to-Treat (ITT) Population: All participants randomized in the study.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 365 participants 367 participants 363 participants 1095 participants
54.2  (11.3) 52.6  (11.4) 52.2  (12.0) 53.0  (11.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 365 participants 367 participants 363 participants 1095 participants
Female
362
  99.2%
365
  99.5%
361
  99.4%
1088
  99.4%
Male
3
   0.8%
2
   0.5%
2
   0.6%
7
   0.6%
1.Primary Outcome
Title Percentage of Participants With Death or Disease Progression According to Independent Review Facility (IRF) Assessment
Hide Description Tumor assessments were performed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a greater than or equal to (≥) 20 percent (%) and 5-millimeter (mm) increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.
Time Frame Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 365 367 363
Measure Type: Number
Unit of Measure: percentage of participants
63.3 64.3 59.8
2.Primary Outcome
Title Progression-Free Survival (PFS) According to IRF Assessment
Hide Description Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding confidence intervals (CIs) were computed using the Brookmeyer-Crowley method.
Time Frame Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 365 367 363
Median (95% Confidence Interval)
Unit of Measure: months
13.7
(12.4 to 14.9)
14.1
(10.9 to 16.8)
15.2
(12.5 to 18.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Non-Inferiority or Equivalence
Comments The study was powered for superiority with target hazard ratio (HR) equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. Non-inferiority was established if the upper bound of the 97.5% CI was less than (<) 1.1765. Superiority was achieved if the upper bound of the 97.5% CI was <1.00.
Statistical Test of Hypothesis P-Value 0.3125
Comments Test and p-value apply for superiority test. Two-sided significance level of 2.5% was used to adjust for independent comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.91
Confidence Interval (2-Sided) 97.5%
0.73 to 1.13
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Placebo vs. Trastuzumab + Taxane
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Non-Inferiority or Equivalence
Comments The study was powered for superiority with target HR equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. Non-inferiority was established if the upper bound of the 97.5% CI was <1.1765. Superiority was achieved if the upper bound of the 97.5% CI was <1.00.
Statistical Test of Hypothesis P-Value 0.1407
Comments Test and p-value apply for superiority test. Two-sided significance level of 2.5% was used to adjust for independent comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.87
Confidence Interval (2-Sided) 97.5%
0.69 to 1.08
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs. Trastuzumab + Taxane
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Trastuzumab Emtansine + Placebo, Trastuzumab Emtansine + Pertuzumab
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Non-Inferiority or Equivalence
Comments The study was powered for superiority with target HR equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
Statistical Test of Hypothesis P-Value 0.3075
Comments Test and p-value apply for superiority test. Primary endpoint did not meet superiority of PFS for trastuzumab emtansine + pertuzumab versus trastuzumab + taxane (two-sided significance level 2.5%); thus, tests and p-value are considered descriptive.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.91
Confidence Interval (2-Sided) 97.5%
0.73 to 1.13
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs. Trastuzumab Emtansine + Placebo
3.Secondary Outcome
Title Percentage of Participants Who Died Prior to Clinical Cutoff
Hide Description The percentage of participants who died prior to clinical cutoff was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.
Time Frame Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 365 367 363
Measure Type: Number
Unit of Measure: percentage of participants
46.3 47.7 46.3
4.Secondary Outcome
Title Overall Survival (OS) at Clinical Cutoff
Hide Description OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
Time Frame Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 365 367 363
Median (95% Confidence Interval)
Unit of Measure: months
50.86
(44.75 to 60.75)
53.68
(48.36 to 64.36)
51.78 [1] 
(47.87 to NA)
[1]
Upper limit of CI was not reached due to low number of participants with events.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6568
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.93
Confidence Interval (2-Sided) 97.5%
0.73 to 1.20
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5691
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.86
Confidence Interval (2-Sided) 97.5%
0.67 to 1.11
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane
5.Secondary Outcome
Title Percentage of Participants With Death or Disease Progression According to Investigator Assessment
Hide Description Tumor assessments were performed by the investigator according to RECIST version 1.1. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.
Time Frame Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 365 367 363
Measure Type: Number
Unit of Measure: percentage of participants
72.1 70.3 67.5
6.Secondary Outcome
Title PFS According to Investigator Assessment
Hide Description Tumor assessments were performed by the investigator according to RECIST version 1.1. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
Time Frame Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 365 367 363
Median (95% Confidence Interval)
Unit of Measure: months
12.5
(10.5 to 13.6)
14.1
(12.2 to 16.7)
14.8
(12.4 to 17.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.85
Confidence Interval (2-Sided) 97.5%
0.69 to 1.04
Estimation Comments Direction of comparison: Trastuzumab Emtasine + Placebo vs Trastuzumab + Taxane
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.77
Confidence Interval (2-Sided) 97.5%
0.63 to 0.95
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane
7.Secondary Outcome
Title Percentage of Participants Experiencing Treatment Failure
Hide Description Treatment failure was defined as the discontinuation of all study medications in the treatment arm for any reason including disease progression, treatment toxicity, death, physician decision, or participant withdrawal. The percentage of participants with treatment failure was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.
Time Frame Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 365 367 363
Measure Type: Number
Unit of Measure: percentage of participants
85.8 82.6 80.2
8.Secondary Outcome
Title Time to Treatment Failure (TTF)
Hide Description Treatment failure was defined as the discontinuation of all study medications in the treatment arm for any reason including disease progression, treatment toxicity, death, physician decision, or participant withdrawal. TTF was defined as the time from randomization to treatment failure. Median TTF was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
Time Frame Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
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Hide Analysis Population Description
ITT Population.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 365 367 363
Median (95% Confidence Interval)
Unit of Measure: months
10.2
(9.2 to 11.8)
12.1
(9.9 to 13.9)
11.8
(9.9 to 14.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval (2-Sided) 97.5%
0.66 to 0.97
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.78
Confidence Interval (2-Sided) 97.5%
0.65 to 0.95
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane
9.Secondary Outcome
Title One-Year Survival Rate
Hide Description The percentage of participants alive at 1 year after randomization was estimated as the one-year survival rate using Kaplan-Meier analysis, and corresponding CIs were computed using Greenwood's estimate of the standard error.
Time Frame From randomization until 1 year
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Hide Analysis Population Description
ITT Population.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 365 367 363
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage probability of being alive
91.4
(88.44 to 94.41)
92.4
(89.62 to 95.15)
91.9
(89.00 to 94.77)
10.Secondary Outcome
Title Percentage of Participants With Grade ≥3 Adverse Events
Hide Description Adverse events were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activity of daily living with inability to perform bathing, dressing and undressing, feeding self, using the toilet, taking medications but not bedridden. Grade 4: An immediate threat to life. Urgent medical intervention is required in order to maintain survival. Grade 5: Death.
Time Frame Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose
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Hide Analysis Population Description
Safety Population: All treated participants. Additionally, 2 participants randomized to trastuzumab+taxane received 3 cycles of trastuzumab emtansine and were included in trastuzumab emtansine+placebo arm. 6 participants randomized to trastuzumab emtansine+placebo received pertuzumab and were included in trastuzumab emtansine+pertuzumab arm.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 353 361 366
Measure Type: Number
Unit of Measure: percentage of participants
54.1 45.4 46.2
11.Secondary Outcome
Title Percentage of Participants Who Died at 2 Years
Hide Description [Not Specified]
Time Frame From randomization until 2 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 365 367 363
Measure Type: Number
Unit of Measure: percentage of participants
20.3 20.2 19.6
12.Secondary Outcome
Title Overall Survival Truncated at 2 Years
Hide Description Overall Survival truncated at 2 years was defined as the percentage of participants alive at 2 years.
Time Frame From randomization until 2 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 365 367 363
Measure Type: Number
Unit of Measure: percentage of participants
79.7 79.8 80.4
13.Secondary Outcome
Title Percentage of Participants With Grade 5 Adverse Events
Hide Description Adverse events were graded according to NCI CTCAE version 4.0. Grade 5 adverse events are those events which led to death.
Time Frame Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 353 361 366
Measure Type: Number
Unit of Measure: percentage of participants
1.7 1.1 1.9
14.Secondary Outcome
Title Percentage of Participants With Grade 3-4 Laboratory Parameters
Hide Description Laboratory results were graded according to NCI CTCAE version 4.0. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activity of daily living with inability to perform bathing, dressing and undressing, feeding self, using the toilet, taking medications but not bedridden. Grade 4: An immediate threat to life. Urgent medical intervention is required in order to maintain survival.
Time Frame Day 1, 8, and 15 of Cycle 1–3 and on Day 1 of each subsequent cycle up to 50 months from randomization until clinical cutoff of 16-Sept-2014
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population. Number of participants analyzed=participants with available data for the outcome.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 352 361 363
Measure Type: Number
Unit of Measure: percentage of participants
Hemoglobin-Low: Grade 3 4.3 5.8 6.9
Neutrophils-Low: Grade 3 20.2 5.5 5.0
Neutrophils-Low: Grade 4 43.8 1.9 0.8
Platelets-Low: Grade 3 0.9 12.7 12.9
Platelets-Low: Grade 4 0.3 2.8 2.5
Alkaline Phosphate-High: Grade 3 1.1 3.9 3.0
Alanine Transaminase-High: Grade 3 3.4 9.1 8.0
Alanine Transaminase-High: Grade 4 0.0 0.3 0.6
Aspartate Aminotransferase-High: Grade 3 1.1 11.9 6.9
Aspartate Aminotransferase-High: Grade 4 0.0 0.3 0.3
Creatinine-High: Grade 3 0.9 0.3 1.1
Creatinine-High: Grade 4 0.0 0.0 0.3
Potassium-Low: Grade 3 4.3 4.7 5.2
Potassium-Low: Grade 4 0.6 1.7 0.6
Total Bilirubin-High: Grade 3 0.3 0.3 0.3
15.Secondary Outcome
Title Percentage of Participants With Decline of ≥2 Points From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status
Hide Description The ECOG performance status is a scale used to quantify cancer participants' general well-being and activities of daily life. The scale ranges from 0 to 5, with 0 denoting perfect health and 5 indicating death. The 6 categories are 0=Asymptomatic (Fully active, able to carry on all predisease activities without restriction), 1=Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), 2=Symptomatic, < 50% in bed during the day (Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours), 3=Symptomatic, > 50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours), 4=Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair), 5=Death.
Time Frame Baseline, Day 1 of every Cycle up to Clinical Data Cut (up to 48 months)
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Hide Analysis Population Description
Safety population
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 353 361 366
Measure Type: Number
Unit of Measure: percentage of participants
7.6 6.1 7.9
16.Secondary Outcome
Title Hospitalization Days
Hide Description Hospitalization was defined as a non-administration-related hospitalization due to serious adverse event, while on study treatment. Reported values represent number of days admitted per participants.
Time Frame Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
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Hide Analysis Population Description
Safety population. Number of participants analyzed=participants with hospitalization and data available for calculation of the parameter.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 353 361 366
Median (Full Range)
Unit of Measure: days
6
(1 to 50)
5
(1 to 117)
8
(1 to 381)
17.Secondary Outcome
Title Percentage of Participants With Hospitalization
Hide Description Hospitalization was defined as a non-administration-related hospitalization due to serious adverse event, while on study treatment.
Time Frame Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety population
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 353 361 366
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
21.8
(17.62 to 26.36)
20.2
(16.20 to 24.71)
22.1
(18.03 to 26.70)
18.Secondary Outcome
Title Percentage of Participants With Objective Response According to IRF Assessment
Hide Description Objective response was defined as having complete response (CR) or partial response (PR), assessed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the objective response rate [ORR]) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.
Time Frame Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
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Hide Analysis Population Description
ITT Population. Only participants with measurable disease at Baseline were included in the analysis.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 287 303 299
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
67.9
(62.26 to 73.31)
59.7
(54.07 to 65.30)
64.2
(58.62 to 69.65)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Response Rate
Estimated Value -8.2
Confidence Interval (2-Sided) 95%
-15.9 to -0.5
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Response Rate
Estimated Value -3.7
Confidence Interval (2-Sided) 95%
-11.4 to 3.9
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Trastuzumab Emtansine + Placebo, Trastuzumab Emtansine + Pertuzumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Response Rate
Estimated Value 4.5
Confidence Interval (2-Sided) 95%
-3.3 to 12.2
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab Emtansine + Placebo
19.Secondary Outcome
Title Percentage of Participants With Objective Response According to Investigator Assessment
Hide Description Objective response was defined as having CR or PR, assessed according to RECIST version 1.1, by investigator. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.
Time Frame Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 365 367 363
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
69.3
(63.74 to 74.52)
64.6
(59.12 to 69.87)
67.5
(62.17 to 72.68)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Response Rate
Estimated Value -4.6
Confidence Interval (2-Sided) 95%
-12.1 to 2.8
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Response Rate
Estimated Value -1.8
Confidence Interval (2-Sided) 95%
-9.2 to 5.7
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Trastuzumab Emtansine + Placebo, Trastuzumab Emtansine + Pertuzumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Response Rate
Estimated Value 2.9
Confidence Interval (2-Sided) 95%
-4.5 to 10.3
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab Emtansine + Placebo
20.Secondary Outcome
Title Duration of Response According to IRF Assessment
Hide Description Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Duration of response was defined as the time from confirmed PR or CR to first documented disease progression or death from any cause. CR was defined as the disappearance of all target lesions and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. Median duration of response was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
Time Frame Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Only participants achieving CR or PR were included in the analysis.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 195 181 192
Median (95% Confidence Interval)
Unit of Measure: months
12.5
(10.5 to 16.6)
20.7
(14.8 to 25.0)
21.2
(15.8 to 29.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.60
Confidence Interval (2-Sided) 97.5%
0.43 to 0.84
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.62
Confidence Interval (2-Sided) 97.5%
0.45 to 0.85
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane
21.Secondary Outcome
Title Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) According to IRF Assessment
Hide Description Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient (20%) increase to qualify for disease progression. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR, PR, or SD was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100.
Time Frame Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
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Hide Analysis Population Description
Data were not analyzed. Protocol Amendment E removed this outcome measure as a secondary endpoint, because it was redundant to another prespecified secondary endpoint.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
22.Secondary Outcome
Title Percentage of Participants Experiencing a Clinically Significant Increase in Taxane-Related Treatment Symptoms as Measured by Taxane Subscale of the Functional Assessment of Cancer Therapy (FACT) Taxane (FACT-TaxS) Score
Hide Description The FACT-Taxane is a self-reported instrument which measures the health-related quality of life (HRQOL) of participants receiving taxane-containing chemotherapy. The FACT-TaxS consists of 16 items including 11 neurotoxicity-related questions and 5 additional questions assessing arthralgia, myalgia, and skin discoloration. Items are rated from 0 (not at all) to 4 (very much) and a total score is inversely derived. Scores may range from 0 to 64, with higher scores indicating fewer/no symptoms. A minimally clinically important difference in treatment-related symptoms was defined as a ≥5% decrease (ie, 3.2 points) in FACT-TaxS score from Baseline. The percentage of participants with treatment-related symptoms was calculated using following formula: [number of participants meeting the above threshold divided by the number analyzed] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.
Time Frame Up to 39 months from randomization until clinical cutoff of 16-Sept-2014 (at Baseline, on Day 1 of Cycles 2 to 8 and every even-numbered cycle thereafter and/or up to 42 days after last dose)
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Hide Analysis Population Description
ITT Population (Protocol Amendment C Subpopulation): All randomized participants who entered the study after Protocol Amendment C.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 173 171 154
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
93.1
(88.48 to 96.06)
60.8
(53.39 to 67.93)
68.8
(61.32 to 75.92)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Symptom Rate
Estimated Value -32.2
Confidence Interval (2-Sided) 95%
-40 to -24
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Symptom Rate
Estimated Value -24.2
Confidence Interval (2-Sided) 95%
-32 to -16
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Trastuzumab Emtansine + Placebo, Trastuzumab Emtansine + Pertuzumab
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Symptom Rate
Estimated Value 8.0
Confidence Interval (2-Sided) 95%
-2.3 to 18.4
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab Emtansine + Placebo
23.Secondary Outcome
Title Percentage of Participants Reporting Nausea According to the Relevant Single Items of The FACT Colorectal Cancel (FACT-C) Module
Hide Description The FACT-C is a self-reported instrument which measures HRQOL pertaining to colorectal cancer. Response options on each question may range from 0 (not at all) to 4 (very much). The percentage of participants with nausea was calculated using following formula: [number of participants with any level of either symptom divided by the number analyzed] multiplied by 100.
Time Frame At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2
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Hide Analysis Population Description
ITT Population (Protocol Amendment C Subpopulation). Only participants with a FACT-C score at the designated visit (n) were included in the analysis.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 173 171 154
Measure Type: Number
Unit of Measure: percentage of participants
Nausea, Baseline (n=166,166,150) 22.3 14.5 21.3
Nausea, Cycle 1 Day 8 (n=121,114,95) 38.0 36.0 52.6
Nausea, Cycle 2 Day 1 (n=147,151,138) 27.2 20.5 36.2
Nausea, Cycle 2 Day 8 (n=122,121,105) 35.2 28.1 45.7
24.Secondary Outcome
Title Percentage of Participants Reporting Diarrhea According to the Relevant Single Items of The FACT-C Module
Hide Description The FACT-C is a self-reported instrument which measures HRQOL pertaining to colorectal cancer. Response options on each question may range from 0 (not at all) to 4 (very much). The percentage of participants with diarrhea was calculated using following formula: [number of participants with any level of either symptom divided by the number analyzed] multiplied by 100.
Time Frame At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population (Protocol Amendment C Subpopulation). Only participants with a FACT-C score at the designated visit (n) were included in the analysis.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 173 171 154
Measure Type: Number
Unit of Measure: percentage of participants
Diarrhea, Baseline (n=173,170,153) 15.0 7.6 11.8
Diarrhea, Cycle 1 Day 8 (n=124,117,98) 34.7 17.9 34.7
Diarrhea, Cycle 2 Day 1 (n=161,160,144) 24.2 11.3 39.6
Diarrhea, Cycle 2 Day 8 (n=125,123,107) 34.4 8.1 41.1
25.Secondary Outcome
Title Percentage of Participants With a Clinically Significant Deterioration in Health Related Quality of Life (HRQoL) as Measured by FACT Breast (FACT-B) Trial Outcome Index-Physical Function Breast (TOI-PFB) Score
Hide Description The FACT-B is a self-reported instrument which measures HRQOL of participants with breast cancer. It consists of 5 subscales including physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and a breast cancer subscale (BCS). The TOI-PFB score is taken by adding the scores from the PWB (7 items), FWB (7 items), and BCS (9 items) subscales. Items are rated from 0 (not at all) to 4 (very much) and a total score is derived. Scores may range from 0 to 92, with higher scores indicating better HRQOL. A 5 point change has been identified as the clinically minimal important difference (CMID) on the FACT-TOI-PFB scale. The percentage of participants with deterioration was calculated as [number of participants meeting the above threshold divided by the number analyzed] multiplied by 100.
Time Frame Up to 39 months from randomization until clinical cutoff of 16-Sept-2014 (at Baseline, on Day 1 of Cycles 2 to 8 and every even-numbered cycle thereafter and/or up to 42 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Number of participants analyzed=participants with baseline and at least one post baseline FACT-B TOI-PFB score.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 327 352 338
Measure Type: Number
Unit of Measure: percentage of participants
61.8 50.9 50.6
26.Secondary Outcome
Title Time to Deterioration in HRQoL as Assessed by FACT-B TOI-PFB Score
Hide Description The FACT-B is a self-reported instrument which measures HRQOL of participants with breast cancer. It consists of 5 subscales including PWB, SWB, EWB, FWB, and BCS. The TOI-PFB score is taken by adding the scores from the PWB (7 items), FWB (7 items), and BCS (9 items) subscales. Items are rated from 0 (not at all) to 4 (very much) and a total score is derived. Scores may range from 0 to 92, with higher scores indicating better HRQOL. A 5 point change has been identified as the clinically minimal important difference (CMID) on the FACT-TOI-PFB scale. Time to deterioration was defined as the time from Baseline until the first decrease in FACT-B TOI-PFB score. Median time to deterioration was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method.
Time Frame Baseline up to 39 months from randomization until clinical cutoff of 16-Sept-2014
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Number of participants analyzed=participants with baseline and at least one post baseline FACT-B TOI-PFB score.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 327 352 338
Median (95% Confidence Interval)
Unit of Measure: months
3.6
(3.0 to 4.4)
7.7
(6.2 to 11.9)
9.0
(5.1 to 14.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.70
Confidence Interval (2-Sided) 95%
0.57 to 0.86
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
Comments Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.68
Confidence Interval (2-Sided) 95%
0.55 to 0.84
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane
27.Secondary Outcome
Title Change From Baseline in Rotterdam Symptom Checklist (RSCL) Activity Level Scale Score
Hide Description The RSCL is a self-reported instrument which consists of 4 domains including physical symptom distress, psychological distress, activity level, and overall global life quality. Only the activity level scale was collected and assessed. Scores may range from 0 to 100, with higher scores indicating increased burden of disease. Mean RSCL activity scale score changes were calculated as [mean score at the assessment visit minus mean score at Baseline]. The higher the score, the higher the level of impairment or burden.
Time Frame Baseline, Cycle 7 (Week 18)
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Hide Analysis Population Description
ITT Population. Here, 'n' signifies the number of participants with available data at baseline and Cycle 7 (Week 18).
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 365 367 363
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline (n=344,355,344)
85.0
(82.9 to 87.2)
85.5
(83.3 to 87.8)
85.7
(83.5 to 87.8)
Change From Baseline at Cycle 7 (n=261,252,261)
-1.6
(-4.2 to 1.0)
2.3
(0.4 to 4.2)
-0.2
(-2.1 to 1.6)
28.Secondary Outcome
Title Change From Baseline in Work Productivity According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score
Hide Description The WPAI is a patient-reported measure which assesses the effect of general health and symptom severity on work productivity and regular activities. The General Health questionnaire asks participants to estimate the number of hours missed from work due to reasons related and unrelated to their health problems, as well as the total number of hours actually worked in the preceding 7-day period. The percentage of participants reporting that they were employed (working for pay) was assessed at baseline was assessed along with Absenteeism (work time missed), Presenteeism (impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work impairment / absenteeism plus presenteeism), and Activity Impairment. The reported changes represent change from baseline at Cycle 7. The score range for the scales of the WPAI is between 0 (no effect) to 100% (max effect)
Time Frame Baseline, Cycle 7 (Week 18)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Number of participants analysed=participants from ITT population who were employed at baseline. Here, 'n' signifies the number of participants with available data at specified category.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 67 64 67
Mean (95% Confidence Interval)
Unit of Measure: percent of work
% Work Time Missed at Baseline (n=66,63,67)
15.3
(9.2 to 21.4)
9.5
(4.2 to 14.8)
13.6
(7.7 to 19.6)
Change in % Work Time Missed (n=35,33,36)
0.4
(-7.3 to 8.2)
-0.0
(-4.5 to 4.5)
-4.3
(-13.0 to 4.6)
% Impairment While Working at Baseline(n=67,64,67)
20.0
(14.1 to 25.9)
15.3
(9.5 to 21.1)
19.9
(13.6 to 26.1)
Change in % Impairment While Working (n=34,32,35)
8.8
(2.0 to 15.6)
-0.3
(-11.0 to 10.5)
-2.7
(-11.0 to 5.2)
% Overall Work Impairment at Baseline (n=65,62,66)
28.5
(20.7 to 36.2)
21.2
(13.8 to 28.7)
28.1
(20.3 to 35.9)
Change in % Overall Work Impairment (n=34,31,35)
9.1
(-0.4 to 18.6)
-1.1
(-13.0 to 11.0)
-4.6
(-14.0 to 5.0)
29.Secondary Outcome
Title Change From Baseline in Activity Impairment According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score
Hide Description The WPAI is a patient-reported measure which assesses the effect of general health and symptom severity on work productivity and regular activities. The General Health questionnaire asks participants to estimate the number of hours missed from work due to reasons related and unrelated to their health problems, as well as the total number of hours actually worked in the preceding 7-day period. The percentage of participants reporting that they were employed (working for pay) was assessed at baseline was assessed along with Absenteeism (work time missed), Presenteeism (impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work impairment / absenteeism plus presenteeism), and Activity Impairment. The reported changes represent change from baseline at Cycle 7. The score range for the scales of the WPAI is between 0 (no effect) to 100% (max effect).
Time Frame Baseline, Cycle 7 (Week 18)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Number of participants analysed=participants from ITT population who reported conduct of daily activities. Here, 'n' signifies the number of participants with available data at specified category.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 312 334 321
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
% Activity Impairment at Baseline (n=312,334,321)
32.9
(29.6 to 36.3)
33.6
(30.2 to 37.0)
32.7
(29.5 to 36.0)
Change in % Activity Impairment (n=227,222,234)
4.5
(0.2 to 8.7)
-5.3
(-9.5 to -1.1)
-3.7
(-7.2 to -0.1)
30.Secondary Outcome
Title Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With High Human Epidermal Growth Factor Receptor 2 (HER2) Messenger Ribonucleic Acid (mRNA) Levels
Hide Description Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100.
Time Frame Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population (High HER2 mRNA Subpopulation): All randomized participants with above-the-median HER2 mRNA expression (value greater than [>] 59.71). Only participants with measurable disease at Baseline were included in the analysis.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 132 136 147
Measure Type: Number
Unit of Measure: percentage of participants
75.0 66.9 63.9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.67
Confidence Interval (2-Sided) 95%
0.40 to 1.15
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane
31.Secondary Outcome
Title Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With Low HER2 mRNA Levels
Hide Description Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100.
Time Frame Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population (Low HER2 mRNA Subpopulation): All randomized participants with below-the-median HER2 mRNA expression (value less than or equal to [≤] 59.71). Only participants with measurable disease at Baseline were included in the analysis.
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 126 147 127
Measure Type: Number
Unit of Measure: percentage of participants
61.9 51.7 66.1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.66
Confidence Interval (2-Sided) 95%
0.41 to 1.07
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane
32.Secondary Outcome
Title Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With High HER2 mRNA Levels
Hide Description Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.
Time Frame Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population (High HER2 mRNA Subpopulation).
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 160 165 173
Measure Type: Number
Unit of Measure: percentage of participants
59.4 57.6 56.1
33.Secondary Outcome
Title PFS According to IRF Assessment Among Those With High HER2 mRNA Levels
Hide Description Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis.
Time Frame Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population (High HER2 mRNA Subpopulation).
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 160 165 173
Median (Full Range)
Unit of Measure: months
15.9
(0.1 to 46.4)
18.6
(0.1 to 46.0)
18.7
(0.1 to 48.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.90
Confidence Interval (2-Sided) 97.5%
0.65 to 1.25
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane
34.Secondary Outcome
Title Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With Low HER2 mRNA Levels
Hide Description Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.
Time Frame Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population (Low HER2 mRNA Subpopulation).
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 170 174 157
Measure Type: Number
Unit of Measure: percentage of participants
66.5 70.1 62.4
35.Secondary Outcome
Title PFS According to IRF Assessment Among Those With Low HER2 mRNA Levels
Hide Description Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis.
Time Frame Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population (Low HER2 mRNA Subpopulation).
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 170 174 157
Median (Full Range)
Unit of Measure: months
12.4
(0.1 to 47.3)
10.2
(0.1 to 43.6)
14.5
(0.1 to 40.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.00
Confidence Interval (2-Sided) 97.5%
0.74 to 1.34
Estimation Comments Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane
36.Secondary Outcome
Title Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With High HER2 mRNA Levels
Hide Description The percentage of participants who died prior to clinical cutoff was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.
Time Frame Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population (High HER2 mRNA Subpopulation).
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 160 165 173
Measure Type: Number
Unit of Measure: percentage of participants
38.8 41.2 45.1
37.Secondary Outcome
Title OS at Clinical Cutoff Among Those With High HER2 mRNA Levels
Hide Description OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis.
Time Frame Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population (High HER2 mRNA Subpopulation).
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 160 165 173
Median (Full Range)
Unit of Measure: months
NA [1] 
(50.86 to NA)
65.97
(54.54 to 67.98)
55.39 [2] 
(48.23 to NA)
[1]
Median duration of OS was not reached due to insufficient follow-up. Upper limit of CI was not reached due to low number of participants with events.
[2]
Upper limit of CI was not reached due to low number of participants with events.
38.Secondary Outcome
Title Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With Low HER2 mRNA Levels
Hide Description The percentage of participants who died prior to clinical cutoff was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.
Time Frame Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population (Low HER2 mRNA Subpopulation).
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 170 174 157
Measure Type: Number
Unit of Measure: percentage of participants
51.8 52.9 45.2
39.Secondary Outcome
Title OS at Clinical Cutoff Among Those With Low HER2 mRNA Levels
Hide Description OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis. Reported upper bound of confidence interval for "Trastuzumab Emtansine + Placebo" and confidence interval values for "Trastuzumab + Taxane" and "Trastuzumab Emtansine + Pertuzumab" are censored values.
Time Frame Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population (Low HER2 mRNA Subpopulation).
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description:
Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed 170 174 157
Median (Full Range)
Unit of Measure: months
43.96
(37.19 to 54.87)
47.84
(42.09 to 53.85)
53.29 [1] 
(46.75 to NA)
[1]
Upper limit of CI was not reached due to low number of participants with events.
Time Frame Up to 70 months from randomization until clinical cutoff of 16 September 2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination).
Adverse Event Reporting Description Safety Population: All randomized participants who received at least one dose of study treatment and the participants were analyzed based on the treatment they actually received (N=353 in Trastuzumab + Taxane arm, N=361 in Trastuzumab Emtansine, Pertuzumab-placebo arm, N=366 in Trastuzumab emtansine + pertuzumab arm).
 
Arm/Group Title Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Hide Arm/Group Description Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy. Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination. Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
All-Cause Mortality
Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   81/353 (22.95%)   86/361 (23.82%)   93/366 (25.41%) 
Blood and lymphatic system disorders       
Febrile neutropenia * 1  13/353 (3.68%)  0/361 (0.00%)  0/366 (0.00%) 
Anaemia * 2  1/353 (0.28%)  5/361 (1.39%)  6/366 (1.64%) 
Neutropenia * 2  5/353 (1.42%)  0/361 (0.00%)  0/366 (0.00%) 
Thrombocytopenia * 2  0/353 (0.00%)  2/361 (0.55%)  2/366 (0.55%) 
Hypercoagulation * 2  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Leukopenia * 2  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Cardiac disorders       
Atrial fibrillation * 1  1/353 (0.28%)  0/361 (0.00%)  1/366 (0.27%) 
Cardiac failure * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Cardiac failure congestive * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Myocardial infarction * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Pericardial effusion * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Supraventricular tachycardia * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Ventricular tachycardia * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Acute Myocardial Infarction * 2  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Ear and labyrinth disorders       
Vertigo * 1  0/353 (0.00%)  0/361 (0.00%)  2/366 (0.55%) 
Eye disorders       
Blindness transient * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Macular hole * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Ocular hypertension * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Gastrointestinal disorders       
Diarrhoea * 1  4/353 (1.13%)  0/361 (0.00%)  0/366 (0.00%) 
Vomiting * 1  1/353 (0.28%)  0/361 (0.00%)  4/366 (1.09%) 
Abdominal pain * 1  2/353 (0.57%)  1/361 (0.28%)  0/366 (0.00%) 
Gastritis * 1  0/353 (0.00%)  0/361 (0.00%)  2/366 (0.55%) 
Rectal haemorrhage * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Anal fistula * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Colitis * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Diverticulum * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Gastric haemorrhage * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Gastric ulcer * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Gastritis erosive * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Large intestine perforation * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Lower gastrointestinal haemorrhage * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Mallory-Weiss syndrome * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Mouth haemorrhage * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Nausea * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Splenic artery aneurysm * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Umbilical hernia * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Upper gastrointestinal haemorrhage * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Abdominal Discomfort * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Ascites * 2  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Gastrointestinal Haemorrhage * 2  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Haemorrhoidal Haemorrhage * 2  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
General disorders       
Pyrexia * 1  2/353 (0.57%)  4/361 (1.11%)  5/366 (1.37%) 
Fatigue * 1  3/353 (0.85%)  1/361 (0.28%)  1/366 (0.27%) 
Non-cardiac chest pain * 1  0/353 (0.00%)  2/361 (0.55%)  1/366 (0.27%) 
Death * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
General physical health deterioration * 1  0/353 (0.00%)  0/361 (0.00%)  2/366 (0.55%) 
Pain * 1  0/353 (0.00%)  0/361 (0.00%)  2/366 (0.55%) 
Asthenia * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Catheter site haematoma * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Malaise * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Oedema * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Peripheral swelling * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Adverse Drug Reaction * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Sudden Death * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Hepatobiliary disorders       
Cholecystitis * 1  0/353 (0.00%)  1/361 (0.28%)  1/366 (0.27%) 
Hepatic Fibrosis * 2  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Hepatic Haematoma * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Immune system disorders       
Hypersensitivity * 1  0/353 (0.00%)  2/361 (0.55%)  2/366 (0.55%) 
Anaphylactic reaction * 1  2/353 (0.57%)  0/361 (0.00%)  1/366 (0.27%) 
Cytokine release syndrome * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Anaphylactic Shock * 2  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Anaphylactoid Reaction * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Infections and infestations       
Pneumonia * 1  4/353 (1.13%)  3/361 (0.83%)  5/366 (1.37%) 
Cellulitis * 1  3/353 (0.85%)  3/361 (0.83%)  1/366 (0.27%) 
Sepsis * 1  1/353 (0.28%)  0/361 (0.00%)  4/366 (1.09%) 
Device related infection * 1  0/353 (0.00%)  1/361 (0.28%)  1/366 (0.27%) 
Gastroenteritis * 1  1/353 (0.28%)  0/361 (0.00%)  2/366 (0.55%) 
Infection * 1  1/353 (0.28%)  1/361 (0.28%)  1/366 (0.27%) 
Neutropenic sepsis * 1  3/353 (0.85%)  0/361 (0.00%)  0/366 (0.00%) 
Septic shock * 1  2/353 (0.57%)  1/361 (0.28%)  1/366 (0.27%) 
Bronchitis * 1  0/353 (0.00%)  0/361 (0.00%)  3/366 (0.82%) 
Herpes zoster * 1  2/353 (0.57%)  0/361 (0.00%)  0/366 (0.00%) 
Upper respiratory tract infection * 1  1/353 (0.28%)  1/361 (0.28%)  0/366 (0.00%) 
Urinary tract infection * 1  2/353 (0.57%)  0/361 (0.00%)  0/366 (0.00%) 
Wound infection * 1  1/353 (0.28%)  1/361 (0.28%)  0/366 (0.00%) 
Arthritis infective * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Atypical pneumonia * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Breast abscess * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Chorioretinitis * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Clostridium difficile colitis * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Clostridium difficile infection * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Cystitis * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Empyema * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Erysipelas * 1  1/353 (0.28%)  1/361 (0.28%)  0/366 (0.00%) 
Escherichia sepsis * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Gastroenteritis viral * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Influenza * 1  1/353 (0.28%)  1/361 (0.28%)  0/366 (0.00%) 
Klebsiella sepsis * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Localised infection * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Lower respiratory tract infection * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Lung infection * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Mastitis * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Nasopharyngitis * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Pneumonia pneumococcal * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Rectal abscess * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Respiratory tract infection * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Streptococcal sepsis * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Tooth infection * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Urosepsis * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Abscess Limb * 2  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Appendicitis Perforated * 2  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Catheter Site Infection * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Skin Infection * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Injury, poisoning and procedural complications       
Infusion related reaction * 1  1/353 (0.28%)  7/361 (1.94%)  13/366 (3.55%) 
Femur fracture * 1  1/353 (0.28%)  0/361 (0.00%)  3/366 (0.82%) 
Pubis fracture * 1  1/353 (0.28%)  0/361 (0.00%)  1/366 (0.27%) 
Arterial injury * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Contusion * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Fall * 1  0/353 (0.00%)  2/361 (0.55%)  0/366 (0.00%) 
Femoral neck fracture * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Gastrointestinal stoma complication * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Hip fracture * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Radiation retinopathy * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Spinal compression fracture * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Subdural haematoma * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Wound secretion * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Abdominal Injury * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Foot Fracture * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Fracture * 2  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Stomal Hernia * 2  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Uncoded serious adverse event * 2 [1]  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Investigations       
Alanine aminotransferase increased * 1  0/353 (0.00%)  0/361 (0.00%)  2/366 (0.55%) 
Aspartate aminotransferase increased * 1  0/353 (0.00%)  0/361 (0.00%)  2/366 (0.55%) 
Body temperature increased * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
International normalised ratio increased * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Oxygen saturation decreased * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Metabolism and nutrition disorders       
Dehydration * 1  1/353 (0.28%)  0/361 (0.00%)  1/366 (0.27%) 
Hyperglycaemia * 1  0/353 (0.00%)  2/361 (0.55%)  0/366 (0.00%) 
Decreased appetite * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Diabetic ketoacidosis * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Hypercalcaemia * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Hypokalaemia * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Hyponatraemia * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Diabetes Mellitus * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  1/353 (0.28%)  2/361 (0.55%)  1/366 (0.27%) 
Back pain * 1  1/353 (0.28%)  1/361 (0.28%)  1/366 (0.27%) 
Bone pain * 1  2/353 (0.57%)  1/361 (0.28%)  0/366 (0.00%) 
Intervertebral disc protrusion * 1  1/353 (0.28%)  1/361 (0.28%)  0/366 (0.00%) 
Exostosis * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Musculoskeletal chest pain * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Musculoskeletal pain * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Neck pain * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Pain in extremity * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Pathological fracture * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Rotator cuff syndrome * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Tenosynovitis * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Acute leukaemia * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Breast neoplasm * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Chronic myeloid leukaemia * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Colon neoplasm * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Lung adenocarcinoma * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Myelodysplastic syndrome * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Squamous cell carcinoma of the cervix * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Tumour haemorrhage * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Uterine leiomyoma * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Basal Cell Carcinoma * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Intracranial Tumour Haemorrhage * 2  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Nervous system disorders       
Headache * 1  0/353 (0.00%)  2/361 (0.55%)  2/366 (0.55%) 
Syncope * 1  0/353 (0.00%)  2/361 (0.55%)  1/366 (0.27%) 
Haemorrhage intracranial * 1  1/353 (0.28%)  1/361 (0.28%)  0/366 (0.00%) 
Cerebrovascular accident * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Cognitive disorder * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Depressed level of consciousness * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Guillain-Barre syndrome * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Lacunar infarction * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Paraparesis * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Peripheral sensory neuropathy * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Presyncope * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Somnolence * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Vascular dementia * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Cerebral Haemorrhage * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Epilepsy * 2  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Neuropathy Peripheral * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Sciatica * 2  1/353 (0.28%)  0/361 (0.00%)  1/366 (0.27%) 
Seizure * 2  1/353 (0.28%)  1/361 (0.28%)  1/366 (0.27%) 
Product Issues       
Device Breakage * 2  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Psychiatric disorders       
Confusional state * 1  0/353 (0.00%)  0/361 (0.00%)  2/366 (0.55%) 
Depression * 1  0/353 (0.00%)  1/361 (0.28%)  2/366 (0.55%) 
Anxiety * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Mental Status Changes * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Suicide Attempt * 2  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Renal and urinary disorders       
Calculus urinary * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Reproductive system and breast disorders       
Menorrhagia * 1  0/353 (0.00%)  1/361 (0.28%)  1/366 (0.27%) 
Endometrial hypertrophy * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Vaginal haemorrhage * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Pleural effusion * 1  3/353 (0.85%)  1/361 (0.28%)  3/366 (0.82%) 
Pulmonary embolism * 1  4/353 (1.13%)  2/361 (0.55%)  1/366 (0.27%) 
Dyspnoea * 1  2/353 (0.57%)  1/361 (0.28%)  1/366 (0.27%) 
Epistaxis * 1  0/353 (0.00%)  1/361 (0.28%)  3/366 (0.82%) 
Interstitial lung disease * 1  1/353 (0.28%)  1/361 (0.28%)  1/366 (0.27%) 
Pneumothorax * 1  0/353 (0.00%)  0/361 (0.00%)  2/366 (0.55%) 
Acute respiratory failure * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Alveolitis allergic * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Chronic obstructive pulmonary disease * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Hypoxia * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Nasal turbinate hypertrophy * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Pneumonitis * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Pulmonary fibrosis * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Respiratory failure * 1  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Acute Pulmonary Oedema * 2  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
Skin and subcutaneous tissue disorders       
Rash * 1  0/353 (0.00%)  2/361 (0.55%)  0/366 (0.00%) 
Dermatomyositis * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Peau d’orange * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Cutaneous Lupus Erythematosus * 2  0/353 (0.00%)  1/361 (0.28%)  1/366 (0.27%) 
Vascular disorders       
Hypertension * 1  1/353 (0.28%)  1/361 (0.28%)  0/366 (0.00%) 
Haematoma * 1  0/353 (0.00%)  2/361 (0.55%)  0/366 (0.00%) 
Haemorrhage * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Hypertensive crisis * 1  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Hypotension * 1  1/353 (0.28%)  0/361 (0.00%)  0/366 (0.00%) 
Aneurysm * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Hypovolaemic Shock * 2  0/353 (0.00%)  0/361 (0.00%)  1/366 (0.27%) 
Orthostatic Hypotension * 2  0/353 (0.00%)  1/361 (0.28%)  0/366 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (17.1)
2
Term from vocabulary, MedDRA (19.0)
[1]
Per investigator, this serious adverse event was, "gamma nail implant broke (status after femur fracture)."
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   342/353 (96.88%)   352/361 (97.51%)   352/366 (96.17%) 
Blood and lymphatic system disorders       
Neutropenia * 1  74/353 (20.96%)  44/361 (12.19%)  37/366 (10.11%) 
Anaemia * 1  39/353 (11.05%)  48/361 (13.30%)  59/366 (16.12%) 
Thrombocytopenia * 1  0/353 (0.00%)  52/361 (14.40%)  61/366 (16.67%) 
Ear and labyrinth disorders       
Vertigo * 2  11/353 (3.12%)  17/361 (4.71%)  21/366 (5.74%) 
Eye disorders       
Lacrimation increased * 1  48/353 (13.60%)  13/361 (3.60%)  19/366 (5.19%) 
Dry eye * 1  13/353 (3.68%)  25/361 (6.93%)  24/366 (6.56%) 
Vision Blurred  2  10/353 (2.83%)  13/361 (3.60%)  19/366 (5.19%) 
Gastrointestinal disorders       
Nausea * 1  131/353 (37.11%)  174/361 (48.20%)  192/366 (52.46%) 
Diarrhoea * 2  173/353 (49.01%)  92/361 (25.48%)  178/366 (48.63%) 
Vomiting * 1  69/353 (19.55%)  80/361 (22.16%)  111/366 (30.33%) 
Constipation * 1  72/353 (20.40%)  82/361 (22.71%)  71/366 (19.40%) 
Stomatitis * 1  57/353 (16.15%)  37/361 (10.25%)  42/366 (11.48%) 
Dyspepsia * 1  38/353 (10.76%)  33/361 (9.14%)  48/366 (13.11%) 
Abdominal pain upper * 1  31/353 (8.78%)  39/361 (10.80%)  46/366 (12.57%) 
Dry mouth * 1  13/353 (3.68%)  52/361 (14.40%)  45/366 (12.30%) 
Abdominal pain * 1  31/353 (8.78%)  35/361 (9.70%)  41/366 (11.20%) 
Gingival bleeding * 1  4/353 (1.13%)  31/361 (8.59%)  25/366 (6.83%) 
Haemorrhoids * 1  9/353 (2.55%)  12/361 (3.32%)  22/366 (6.01%) 
General disorders       
Fatigue * 2  128/353 (36.26%)  120/361 (33.24%)  130/366 (35.52%) 
Pyrexia * 1  59/353 (16.71%)  96/361 (26.59%)  118/366 (32.24%) 
Asthenia * 1  57/353 (16.15%)  62/361 (17.17%)  63/366 (17.21%) 
Chills * 1  14/353 (3.97%)  55/361 (15.24%)  97/366 (26.50%) 
Oedema peripheral * 1  98/353 (27.76%)  37/361 (10.25%)  35/366 (9.56%) 
Mucosal inflammation * 1  40/353 (11.33%)  29/361 (8.03%)  36/366 (9.84%) 
Influenza like illness * 1  17/353 (4.82%)  31/361 (8.59%)  32/366 (8.74%) 
Non-cardiac chest pain * 1  24/353 (6.80%)  25/361 (6.93%)  27/366 (7.38%) 
Pain * 1  29/353 (8.22%)  26/361 (7.20%)  19/366 (5.19%) 
Oedema * 1  31/353 (8.78%)  11/361 (3.05%)  3/366 (0.82%) 
Infections and infestations       
Upper respiratory tract infection * 1  55/353 (15.58%)  50/361 (13.85%)  66/366 (18.03%) 
Nasopharyngitis * 1  49/353 (13.88%)  52/361 (14.40%)  66/366 (18.03%) 
Urinary tract infection * 1  29/353 (8.22%)  31/361 (8.59%)  41/366 (11.20%) 
Rhinitis * 1  18/353 (5.10%)  25/361 (6.93%)  24/366 (6.56%) 
Influenza * 1  14/353 (3.97%)  22/361 (6.09%)  25/366 (6.83%) 
Paronychia * 1  22/353 (6.23%)  8/361 (2.22%)  30/366 (8.20%) 
Pharyngitis * 1  14/353 (3.97%)  19/361 (5.26%)  17/366 (4.64%) 
Conjunctivitis * 1  21/353 (5.95%)  14/361 (3.88%)  17/366 (4.64%) 
Bronchitis  2  14/353 (3.97%)  9/361 (2.49%)  20/366 (5.46%) 
Investigations       
Aspartate aminotransferase increased * 1  9/353 (2.55%)  54/361 (14.96%)  28/366 (7.65%) 
Alanine aminotranseferase increased * 1  10/353 (2.83%)  41/361 (11.36%)  35/366 (9.56%) 
Weight decreased * 1  7/353 (1.98%)  24/361 (6.65%)  30/366 (8.20%) 
Ejection fraction decreased * 1  31/353 (8.78%)  7/361 (1.94%)  16/366 (4.37%) 
Gamma- glutamyltranseferase increased * 1  1/353 (0.28%)  30/361 (8.31%)  17/366 (4.64%) 
Metabolism and nutrition disorders       
Decreased appetite * 1  76/353 (21.53%)  84/361 (23.27%)  84/366 (22.95%) 
Hypokalaemia * 1  15/353 (4.25%)  19/361 (5.26%)  30/366 (8.20%) 
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  91/353 (25.78%)  83/361 (22.99%)  71/366 (19.40%) 
Myalgia * 1  82/353 (23.23%)  66/361 (18.28%)  61/366 (16.67%) 
Back pain * 1  46/353 (13.03%)  60/361 (16.62%)  63/366 (17.21%) 
Pain in extremity * 1  48/353 (13.60%)  53/361 (14.68%)  54/366 (14.75%) 
Muscle spasms * 1  15/353 (4.25%)  32/361 (8.86%)  62/366 (16.94%) 
Musculoskeletal pain * 1  23/353 (6.52%)  30/361 (8.31%)  37/366 (10.11%) 
Bone pain * 1  33/353 (9.35%)  17/361 (4.71%)  29/366 (7.92%) 
Musculoskeletal chest pain * 1  17/353 (4.82%)  13/361 (3.60%)  20/366 (5.46%) 
Neck Pain * 1  12/353 (3.40%)  12/361 (3.32%)  24/366 (6.56%) 
Nervous system disorders       
Headache * 1  80/353 (22.66%)  116/361 (32.13%)  120/366 (32.79%) 
Neuropathy peripheral * 1  99/353 (28.05%)  52/361 (14.40%)  69/366 (18.85%) 
Peripheral sensory neuropathy * 1  70/353 (19.83%)  47/361 (13.02%)  46/366 (12.57%) 
Dysgeusia * 1  54/353 (15.30%)  30/361 (8.31%)  50/366 (13.66%) 
Paraesthesia * 1  41/353 (11.61%)  31/361 (8.59%)  43/366 (11.75%) 
Dizziness * 1  35/353 (9.92%)  38/361 (10.53%)  38/366 (10.38%) 
Psychiatric disorders       
Insomnia * 1  51/353 (14.45%)  51/361 (14.13%)  52/366 (14.21%) 
Anxiety * 1  22/353 (6.23%)  26/361 (7.20%)  33/366 (9.02%) 
Depression * 1  17/353 (4.82%)  34/361 (9.42%)  20/366 (5.46%) 
Reproductive system and breast disorders       
Breast pain * 1  18/353 (5.10%)  13/361 (3.60%)  16/366 (4.37%) 
Respiratory, thoracic and mediastinal disorders       
Epistaxis * 1  53/353 (15.01%)  113/361 (31.30%)  127/366 (34.70%) 
Cough * 1  74/353 (20.96%)  72/361 (19.94%)  79/366 (21.58%) 
Dyspnoea * 1  56/353 (15.86%)  42/361 (11.63%)  53/366 (14.48%) 
Oropharyngeal pain * 1  29/353 (8.22%)  31/361 (8.59%)  30/366 (8.20%) 
Rhinorrhoea * 1  26/353 (7.37%)  21/361 (5.82%)  32/366 (8.74%) 
Skin and subcutaneous tissue disorders       
Alopecia * 1  212/353 (60.06%)  26/361 (7.20%)  33/366 (9.02%) 
Rash * 1  86/353 (24.36%)  62/361 (17.17%)  89/366 (24.32%) 
Pruritus * 1  32/353 (9.07%)  28/361 (7.76%)  51/366 (13.93%) 
Nail disorder * 1  39/353 (11.05%)  11/361 (3.05%)  19/366 (5.19%) 
Dry skin * 1  24/353 (6.80%)  24/361 (6.65%)  29/366 (7.92%) 
Erythema * 1  24/353 (6.80%)  13/361 (3.60%)  20/366 (5.46%) 
Dermatitis acneiform * 1  6/353 (1.70%)  16/361 (4.43%)  27/366 (7.38%) 
Palmar-plantar erythrodysaesthesia syndrome * 1  26/353 (7.37%)  6/361 (1.66%)  11/366 (3.01%) 
Nail discolouration * 1  25/353 (7.08%)  5/361 (1.39%)  1/366 (0.27%) 
Onychoclasis * 2  13/353 (3.68%)  19/361 (5.26%)  17/366 (4.64%) 
Vascular disorders       
Hypertension * 1  19/353 (5.38%)  37/361 (10.25%)  43/366 (11.75%) 
Hot flush * 1  27/353 (7.65%)  16/361 (4.43%)  12/366 (3.28%) 
Lymphoedema * 1  27/353 (7.65%)  7/361 (1.94%)  8/366 (2.19%) 
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (17.1)
2
Term from vocabulary, MedDRA (19.0)
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 Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
Name/Title: Medical Communications
Organization: Hoffmann-La Roche
Phone: 800-821-8590
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01120184     History of Changes
Other Study ID Numbers: BO22589
2009-017905-13 ( EudraCT Number )
First Submitted: April 28, 2010
First Posted: May 10, 2010
Results First Submitted: May 2, 2016
Results First Posted: February 23, 2017
Last Update Posted: November 7, 2017