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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)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01120184
First Posted: May 10, 2010
Last Update Posted: November 7, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Hoffmann-La Roche
Results First Submitted: May 2, 2016  
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

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Participant Flow:   Overall Study
    Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab
STARTED   365   367   363 
Treated   355   365   360 
COMPLETED   0   0   0 
NOT COMPLETED   365   367   363 
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 



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-Treat (ITT) Population: All participants randomized in the study.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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 Total of all reporting groups

Baseline Measures
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab   Total 
Overall Participants Analyzed 
[Units: Participants]
 365   367   363   1095 
Age 
[Units: Years]
Mean (Standard Deviation)
 54.2  (11.3)   52.6  (11.4)   52.2  (12.0)   53.0  (11.6) 
Sex: Female, Male 
[Units: Participants]
Count of 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% 


  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Percentage of Participants With Death or Disease Progression According to Independent Review Facility (IRF) Assessment   [ 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) ]

Measure Type Primary
Measure Title Percentage of Participants With Death or Disease Progression According to Independent Review Facility (IRF) Assessment
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 365   367   363 
Percentage of Participants With Death or Disease Progression According to Independent Review Facility (IRF) Assessment 
[Units: Percentage of participants]
 63.3   64.3   59.8 

No statistical analysis provided for Percentage of Participants With Death or Disease Progression According to Independent Review Facility (IRF) Assessment



2.  Primary:   Progression-Free Survival (PFS) According to IRF Assessment   [ 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) ]

Measure Type Primary
Measure Title Progression-Free Survival (PFS) According to IRF Assessment
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 365   367   363 
Progression-Free Survival (PFS) According to IRF Assessment 
[Units: Months]
Median (95% Confidence Interval)
 13.7 
 (12.4 to 14.9) 
 14.1 
 (10.9 to 16.8) 
 15.2 
 (12.5 to 18.8) 


Statistical Analysis 1 for Progression-Free Survival (PFS) According to IRF Assessment
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Placebo
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical Method [3] Log Rank
P Value [4] 0.3125
Hazard Ratio (HR) [5] 0.91
97.5% Confidence Interval 0.73 to 1.13
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  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.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  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.
[5] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Placebo vs. Trastuzumab + Taxane

Statistical Analysis 2 for Progression-Free Survival (PFS) According to IRF Assessment
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Pertuzumab
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical Method [3] Log Rank
P Value [4] 0.1407
Hazard Ratio (HR) [5] 0.87
97.5% Confidence Interval 0.69 to 1.08
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  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.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  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.
[5] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs. Trastuzumab + Taxane

Statistical Analysis 3 for Progression-Free Survival (PFS) According to IRF Assessment
Groups [1] Trastuzumab Emtansine + Placebo vs. Trastuzumab Emtansine + Pertuzumab
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical Method [3] Log Rank
P Value [4] 0.3075
Hazard Ratio (HR) [5] 0.91
97.5% Confidence Interval 0.73 to 1.13
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  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.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  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.
[5] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs. Trastuzumab Emtansine + Placebo



3.  Secondary:   Percentage of Participants Who Died Prior to Clinical Cutoff   [ 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) ]

Measure Type Secondary
Measure Title Percentage of Participants Who Died Prior to Clinical Cutoff
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 365   367   363 
Percentage of Participants Who Died Prior to Clinical Cutoff 
[Units: Percentage of participants]
 46.3   47.7   46.3 

No statistical analysis provided for Percentage of Participants Who Died Prior to Clinical Cutoff



4.  Secondary:   Overall Survival (OS) at Clinical Cutoff   [ 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) ]

Measure Type Secondary
Measure Title Overall Survival (OS) at Clinical Cutoff
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 365   367   363 
Overall Survival (OS) at Clinical Cutoff 
[Units: Months]
Median (95% Confidence Interval)
 50.86 
 (44.75 to 60.75) 
 53.68 
 (48.36 to 64.36) 
 51.78 [1] 
 (47.87 to N/A) 
[1] Upper limit of CI was not reached due to low number of participants with events.


Statistical Analysis 1 for Overall Survival (OS) at Clinical Cutoff
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.6568
Hazard Ratio (HR) [5] 0.93
97.5% Confidence Interval 0.73 to 1.20
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2 for Overall Survival (OS) at Clinical Cutoff
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Pertuzumab
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.5691
Hazard Ratio (HR) [5] 0.86
97.5% Confidence Interval 0.67 to 1.11
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane



5.  Secondary:   Percentage of Participants With Death or Disease Progression According to Investigator Assessment   [ 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) ]

Measure Type Secondary
Measure Title Percentage of Participants With Death or Disease Progression According to Investigator Assessment
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 365   367   363 
Percentage of Participants With Death or Disease Progression According to Investigator Assessment 
[Units: Percentage of participants]
 72.1   70.3   67.5 

No statistical analysis provided for Percentage of Participants With Death or Disease Progression According to Investigator Assessment



6.  Secondary:   PFS According to Investigator Assessment   [ 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) ]

Measure Type Secondary
Measure Title PFS According to Investigator Assessment
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 365   367   363 
PFS According to Investigator Assessment 
[Units: Months]
Median (95% Confidence Interval)
 12.5 
 (10.5 to 13.6) 
 14.1 
 (12.2 to 16.7) 
 14.8 
 (12.4 to 17.8) 


Statistical Analysis 1 for PFS According to Investigator Assessment
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Placebo
Statistical Test Type [2] Superiority or Other
Hazard Ratio (HR) [3] 0.85
97.5% Confidence Interval 0.69 to 1.04
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtasine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2 for PFS According to Investigator Assessment
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Pertuzumab
Statistical Test Type [2] Superiority or Other
Hazard Ratio (HR) [3] 0.77
97.5% Confidence Interval 0.63 to 0.95
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane



7.  Secondary:   Percentage of Participants Experiencing Treatment Failure   [ Time Frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 ]

Measure Type Secondary
Measure Title Percentage of Participants Experiencing Treatment Failure
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 365   367   363 
Percentage of Participants Experiencing Treatment Failure 
[Units: Percentage of participants]
 85.8   82.6   80.2 

No statistical analysis provided for Percentage of Participants Experiencing Treatment Failure



8.  Secondary:   Time to Treatment Failure (TTF)   [ Time Frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 ]

Measure Type Secondary
Measure Title Time to Treatment Failure (TTF)
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 365   367   363 
Time to Treatment Failure (TTF) 
[Units: Months]
Median (95% Confidence Interval)
 10.2 
 (9.2 to 11.8) 
 12.1 
 (9.9 to 13.9) 
 11.8 
 (9.9 to 14.2) 


Statistical Analysis 1 for Time to Treatment Failure (TTF)
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Placebo
Statistical Test Type [2] Superiority or Other
Hazard Ratio (HR) [3] 0.80
97.5% Confidence Interval 0.66 to 0.97
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2 for Time to Treatment Failure (TTF)
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Pertuzumab
Statistical Test Type [2] Superiority or Other
Hazard Ratio (HR) [3] 0.78
97.5% Confidence Interval 0.65 to 0.95
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane



9.  Secondary:   One-Year Survival Rate   [ Time Frame: From randomization until 1 year ]

Measure Type Secondary
Measure Title One-Year Survival Rate
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 365   367   363 
One-Year Survival Rate 
[Units: Percentage probability of being alive]
Number (95% Confidence Interval)
 91.4 
 (88.44 to 94.41) 
 92.4 
 (89.62 to 95.15) 
 91.9 
 (89.00 to 94.77) 

No statistical analysis provided for One-Year Survival Rate



10.  Secondary:   Percentage of Participants With Grade ≥3 Adverse Events   [ Time Frame: Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose ]

Measure Type Secondary
Measure Title Percentage of Participants With Grade ≥3 Adverse Events
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 353   361   366 
Percentage of Participants With Grade ≥3 Adverse Events 
[Units: Percentage of participants]
 54.1   45.4   46.2 

No statistical analysis provided for Percentage of Participants With Grade ≥3 Adverse Events



11.  Secondary:   Percentage of Participants Who Died at 2 Years   [ Time Frame: From randomization until 2 years ]

Measure Type Secondary
Measure Title Percentage of Participants Who Died at 2 Years
Measure Description No text entered.
Time Frame From randomization until 2 years  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 365   367   363 
Percentage of Participants Who Died at 2 Years 
[Units: Percentage of participants]
 20.3   20.2   19.6 

No statistical analysis provided for Percentage of Participants Who Died at 2 Years



12.  Secondary:   Overall Survival Truncated at 2 Years   [ Time Frame: From randomization until 2 years ]

Measure Type Secondary
Measure Title Overall Survival Truncated at 2 Years
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 365   367   363 
Overall Survival Truncated at 2 Years 
[Units: Percentage of participants]
 79.7   79.8   80.4 

No statistical analysis provided for Overall Survival Truncated at 2 Years



13.  Secondary:   Percentage of Participants With Grade 5 Adverse Events   [ Time Frame: Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose) ]

Measure Type Secondary
Measure Title Percentage of Participants With Grade 5 Adverse Events
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 353   361   366 
Percentage of Participants With Grade 5 Adverse Events 
[Units: Percentage of participants]
 1.7   1.1   1.9 

No statistical analysis provided for Percentage of Participants With Grade 5 Adverse Events



14.  Secondary:   Percentage of Participants With Grade 3-4 Laboratory Parameters   [ 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 ]

Measure Type Secondary
Measure Title Percentage of Participants With Grade 3-4 Laboratory Parameters
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population. Number of participants analyzed=participants with available data for the outcome.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 352   361   363 
Percentage of Participants With Grade 3-4 Laboratory Parameters 
[Units: 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 

No statistical analysis provided for Percentage of Participants With Grade 3-4 Laboratory Parameters



15.  Secondary:   Percentage of Participants With Decline of ≥2 Points From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status   [ Time Frame: Baseline, Day 1 of every Cycle up to Clinical Data Cut (up to 48 months) ]

Measure Type Secondary
Measure Title Percentage of Participants With Decline of ≥2 Points From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 353   361   366 
Percentage of Participants With Decline of ≥2 Points From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status 
[Units: Percentage of participants]
 7.6   6.1   7.9 

No statistical analysis provided for Percentage of Participants With Decline of ≥2 Points From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status



16.  Secondary:   Hospitalization Days   [ Time Frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 ]

Measure Type Secondary
Measure Title Hospitalization Days
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population. Number of participants analyzed=participants with hospitalization and data available for calculation of the parameter.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 353   361   366 
Hospitalization Days 
[Units: Days]
Median (Full Range)
 6 
 (1 to 50) 
 5 
 (1 to 117) 
 8 
 (1 to 381) 

No statistical analysis provided for Hospitalization Days



17.  Secondary:   Percentage of Participants With Hospitalization   [ Time Frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 ]

Measure Type Secondary
Measure Title Percentage of Participants With Hospitalization
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 353   361   366 
Percentage of Participants With Hospitalization 
[Units: Percentage of participants]
Number (95% Confidence Interval)
 21.8 
 (17.62 to 26.36) 
 20.2 
 (16.20 to 24.71) 
 22.1 
 (18.03 to 26.70) 

No statistical analysis provided for Percentage of Participants With Hospitalization



18.  Secondary:   Percentage of Participants With Objective Response According to IRF Assessment   [ 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) ]

Measure Type Secondary
Measure Title Percentage of Participants With Objective Response According to IRF Assessment
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population. Only participants with measurable disease at Baseline were included in the analysis.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 287   303   299 
Percentage of Participants With Objective Response According to IRF Assessment 
[Units: Percentage of participants]
Number (95% Confidence Interval)
 67.9 
 (62.26 to 73.31) 
 59.7 
 (54.07 to 65.30) 
 64.2 
 (58.62 to 69.65) 


Statistical Analysis 1 for Percentage of Participants With Objective Response According to IRF Assessment
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Placebo
Statistical Test Type [2] Superiority or Other
Difference in Response Rate [3] -8.2
95% Confidence Interval -15.9 to -0.5
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2 for Percentage of Participants With Objective Response According to IRF Assessment
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Pertuzumab
Statistical Test Type [2] Superiority or Other
Difference in Response Rate [3] -3.7
95% Confidence Interval -11.4 to 3.9
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane

Statistical Analysis 3 for Percentage of Participants With Objective Response According to IRF Assessment
Groups [1] Trastuzumab Emtansine + Placebo vs. Trastuzumab Emtansine + Pertuzumab
Statistical Test Type [2] Superiority or Other
Difference in Response Rate [3] 4.5
95% Confidence Interval -3.3 to 12.2
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab Emtansine + Placebo



19.  Secondary:   Percentage of Participants With Objective Response According to Investigator Assessment   [ 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) ]

Measure Type Secondary
Measure Title Percentage of Participants With Objective Response According to Investigator Assessment
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 365   367   363 
Percentage of Participants With Objective Response According to Investigator Assessment 
[Units: Percentage of participants]
Number (95% Confidence Interval)
 69.3 
 (63.74 to 74.52) 
 64.6 
 (59.12 to 69.87) 
 67.5 
 (62.17 to 72.68) 


Statistical Analysis 1 for Percentage of Participants With Objective Response According to Investigator Assessment
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Placebo
Statistical Test Type [2] Superiority or Other
Difference in Response Rate [3] -4.6
95% Confidence Interval -12.1 to 2.8
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2 for Percentage of Participants With Objective Response According to Investigator Assessment
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Pertuzumab
Statistical Test Type [2] Superiority or Other
Difference in Response Rate [3] -1.8
95% Confidence Interval -9.2 to 5.7
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane

Statistical Analysis 3 for Percentage of Participants With Objective Response According to Investigator Assessment
Groups [1] Trastuzumab Emtansine + Placebo vs. Trastuzumab Emtansine + Pertuzumab
Statistical Test Type [2] Superiority or Other
Difference in Response Rate [3] 2.9
95% Confidence Interval -4.5 to 10.3
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab Emtansine + Placebo



20.  Secondary:   Duration of Response According to IRF Assessment   [ 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) ]

Measure Type Secondary
Measure Title Duration of Response According to IRF Assessment
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population. Only participants achieving CR or PR were included in the analysis.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 195   181   192 
Duration of Response According to IRF Assessment 
[Units: Months]
Median (95% Confidence Interval)
 12.5 
 (10.5 to 16.6) 
 20.7 
 (14.8 to 25.0) 
 21.2 
 (15.8 to 29.3) 


Statistical Analysis 1 for Duration of Response According to IRF Assessment
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Placebo
Statistical Test Type [2] Superiority or Other
Hazard Ratio (HR) [3] 0.60
97.5% Confidence Interval 0.43 to 0.84
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2 for Duration of Response According to IRF Assessment
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Pertuzumab
Statistical Test Type [2] Superiority or Other
Hazard Ratio (HR) [3] 0.62
97.5% Confidence Interval 0.45 to 0.85
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane



21.  Secondary:   Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) According to IRF Assessment   [ 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) ]

Measure Type Secondary
Measure Title Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) According to IRF Assessment
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Data were not analyzed. Protocol Amendment E removed this outcome measure as a secondary endpoint, because it was redundant to another prespecified secondary endpoint.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 0   0   0 
Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) According to IRF Assessment          

No statistical analysis provided for Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) According to IRF Assessment



22.  Secondary:   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   [ 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) ]

Measure Type Secondary
Measure 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
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population (Protocol Amendment C Subpopulation): All randomized participants who entered the study after Protocol Amendment C.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 173   171   154 
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 
[Units: Percentage of participants]
Number (95% Confidence Interval)
 93.1 
 (88.48 to 96.06) 
 60.8 
 (53.39 to 67.93) 
 68.8 
 (61.32 to 75.92) 


Statistical Analysis 1 for 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
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Placebo
Statistical Test Type [2] Superiority or Other
Difference in Symptom Rate [3] -32.2
95% Confidence Interval -40 to -24
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2 for 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
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Pertuzumab
Statistical Test Type [2] Superiority or Other
Difference in Symptom Rate [3] -24.2
95% Confidence Interval -32 to -16
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane

Statistical Analysis 3 for 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
Groups [1] Trastuzumab Emtansine + Placebo vs. Trastuzumab Emtansine + Pertuzumab
Statistical Test Type [2] Superiority or Other
Difference in Symptom Rate [3] 8.0
95% Confidence Interval -2.3 to 18.4
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab Emtansine + Placebo



23.  Secondary:   Percentage of Participants Reporting Nausea According to the Relevant Single Items of The FACT Colorectal Cancel (FACT-C) Module   [ Time Frame: At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2 ]

Measure Type Secondary
Measure Title Percentage of Participants Reporting Nausea According to the Relevant Single Items of The FACT Colorectal Cancel (FACT-C) Module
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population (Protocol Amendment C Subpopulation). Only participants with a FACT-C score at the designated visit (n) were included in the analysis.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 173   171   154 
Percentage of Participants Reporting Nausea According to the Relevant Single Items of The FACT Colorectal Cancel (FACT-C) Module 
[Units: 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 

No statistical analysis provided for Percentage of Participants Reporting Nausea According to the Relevant Single Items of The FACT Colorectal Cancel (FACT-C) Module



24.  Secondary:   Percentage of Participants Reporting Diarrhea According to the Relevant Single Items of The FACT-C Module   [ Time Frame: At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2 ]

Measure Type Secondary
Measure Title Percentage of Participants Reporting Diarrhea According to the Relevant Single Items of The FACT-C Module
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population (Protocol Amendment C Subpopulation). Only participants with a FACT-C score at the designated visit (n) were included in the analysis.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 173   171   154 
Percentage of Participants Reporting Diarrhea According to the Relevant Single Items of The FACT-C Module 
[Units: 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 

No statistical analysis provided for Percentage of Participants Reporting Diarrhea According to the Relevant Single Items of The FACT-C Module



25.  Secondary:   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   [ 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) ]

Measure Type Secondary
Measure 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
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population. Number of participants analyzed=participants with baseline and at least one post baseline FACT-B TOI-PFB score.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 327   352   338 
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 
[Units: Percentage of participants]
 61.8   50.9   50.6 

No statistical analysis provided for 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



26.  Secondary:   Time to Deterioration in HRQoL as Assessed by FACT-B TOI-PFB Score   [ Time Frame: Baseline up to 39 months from randomization until clinical cutoff of 16-Sept-2014 ]

Measure Type Secondary
Measure Title Time to Deterioration in HRQoL as Assessed by FACT-B TOI-PFB Score
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population. Number of participants analyzed=participants with baseline and at least one post baseline FACT-B TOI-PFB score.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 327   352   338 
Time to Deterioration in HRQoL as Assessed by FACT-B TOI-PFB Score 
[Units: Months]
Median (95% Confidence Interval)
 3.6 
 (3.0 to 4.4) 
 7.7 
 (6.2 to 11.9) 
 9.0 
 (5.1 to 14.5) 


Statistical Analysis 1 for Time to Deterioration in HRQoL as Assessed by FACT-B TOI-PFB Score
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Placebo
Statistical Test Type [2] Superiority or Other
Hazard Ratio (HR) [3] 0.70
95% Confidence Interval 0.57 to 0.86
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2 for Time to Deterioration in HRQoL as Assessed by FACT-B TOI-PFB Score
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Pertuzumab
Statistical Test Type [2] Superiority or Other
Hazard Ratio (HR) [3] 0.68
95% Confidence Interval 0.55 to 0.84
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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).
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane



27.  Secondary:   Change From Baseline in Rotterdam Symptom Checklist (RSCL) Activity Level Scale Score   [ Time Frame: Baseline, Cycle 7 (Week 18) ]

Measure Type Secondary
Measure Title Change From Baseline in Rotterdam Symptom Checklist (RSCL) Activity Level Scale Score
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population. Here, 'n' signifies the number of participants with available data at baseline and Cycle 7 (Week 18).

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 365   367   363 
Change From Baseline in Rotterdam Symptom Checklist (RSCL) Activity Level Scale Score 
[Units: Units on a scale]
Mean (95% Confidence Interval)
     
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) 

No statistical analysis provided for Change From Baseline in Rotterdam Symptom Checklist (RSCL) Activity Level Scale Score



28.  Secondary:   Change From Baseline in Work Productivity According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score   [ Time Frame: Baseline, Cycle 7 (Week 18) ]

Measure Type Secondary
Measure Title Change From Baseline in Work Productivity According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 67   64   67 
Change From Baseline in Work Productivity According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score 
[Units: Percent of work]
Mean (95% Confidence Interval)
     
% 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) 

No statistical analysis provided for Change From Baseline in Work Productivity According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score



29.  Secondary:   Change From Baseline in Activity Impairment According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score   [ Time Frame: Baseline, Cycle 7 (Week 18) ]

Measure Type Secondary
Measure Title Change From Baseline in Activity Impairment According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 312   334   321 
Change From Baseline in Activity Impairment According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score 
[Units: Units on a scale]
Mean (95% Confidence Interval)
     
% 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) 

No statistical analysis provided for Change From Baseline in Activity Impairment According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score



30.  Secondary:   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   [ 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) ]

Measure Type Secondary
Measure 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
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 132   136   147 
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 
[Units: Percentage of participants]
 75.0   66.9   63.9 


Statistical Analysis 1 for 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
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Placebo
Statistical Test Type [2] Superiority or Other
Odds Ratio (OR) [3] 0.67
95% Confidence Interval 0.40 to 1.15
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane



31.  Secondary:   Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With Low HER2 mRNA Levels   [ 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) ]

Measure Type Secondary
Measure Title Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With Low HER2 mRNA Levels
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 126   147   127 
Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With Low HER2 mRNA Levels 
[Units: Percentage of participants]
 61.9   51.7   66.1 


Statistical Analysis 1 for Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With Low HER2 mRNA Levels
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Placebo
Statistical Test Type [2] Superiority or Other
Odds Ratio (OR) [3] 0.66
95% Confidence Interval 0.41 to 1.07
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane



32.  Secondary:   Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With High HER2 mRNA Levels   [ 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) ]

Measure Type Secondary
Measure Title Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With High HER2 mRNA Levels
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population (High HER2 mRNA Subpopulation).

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 160   165   173 
Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With High HER2 mRNA Levels 
[Units: Percentage of participants]
 59.4   57.6   56.1 

No statistical analysis provided for Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With High HER2 mRNA Levels



33.  Secondary:   PFS According to IRF Assessment Among Those With High HER2 mRNA Levels   [ 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) ]

Measure Type Secondary
Measure Title PFS According to IRF Assessment Among Those With High HER2 mRNA Levels
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population (High HER2 mRNA Subpopulation).

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 160   165   173 
PFS According to IRF Assessment Among Those With High HER2 mRNA Levels 
[Units: Months]
Median (Full Range)
 15.9 
 (0.1 to 46.4) 
 18.6 
 (0.1 to 46.0) 
 18.7 
 (0.1 to 48.1) 


Statistical Analysis 1 for PFS According to IRF Assessment Among Those With High HER2 mRNA Levels
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Placebo
Statistical Test Type [2] Superiority or Other
Hazard Ratio (HR) [3] 0.90
97.5% Confidence Interval 0.65 to 1.25
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane



34.  Secondary:   Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With Low HER2 mRNA Levels   [ 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) ]

Measure Type Secondary
Measure Title Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With Low HER2 mRNA Levels
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population (Low HER2 mRNA Subpopulation).

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 170   174   157 
Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With Low HER2 mRNA Levels 
[Units: Percentage of participants]
 66.5   70.1   62.4 

No statistical analysis provided for Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With Low HER2 mRNA Levels



35.  Secondary:   PFS According to IRF Assessment Among Those With Low HER2 mRNA Levels   [ 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) ]

Measure Type Secondary
Measure Title PFS According to IRF Assessment Among Those With Low HER2 mRNA Levels
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population (Low HER2 mRNA Subpopulation).

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 170   174   157 
PFS According to IRF Assessment Among Those With Low HER2 mRNA Levels 
[Units: Months]
Median (Full Range)
 12.4 
 (0.1 to 47.3) 
 10.2 
 (0.1 to 43.6) 
 14.5 
 (0.1 to 40.7) 


Statistical Analysis 1 for PFS According to IRF Assessment Among Those With Low HER2 mRNA Levels
Groups [1] Trastuzumab + Taxane vs. Trastuzumab Emtansine + Placebo
Statistical Test Type [2] Superiority or Other
Hazard Ratio (HR) [3] 1.00
97.5% Confidence Interval 0.74 to 1.34
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant estimation information:
  Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane



36.  Secondary:   Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With High HER2 mRNA Levels   [ 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) ]

Measure Type Secondary
Measure Title Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With High HER2 mRNA Levels
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population (High HER2 mRNA Subpopulation).

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 160   165   173 
Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With High HER2 mRNA Levels 
[Units: Percentage of participants]
 38.8   41.2   45.1 

No statistical analysis provided for Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With High HER2 mRNA Levels



37.  Secondary:   OS at Clinical Cutoff Among Those With High HER2 mRNA Levels   [ 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) ]

Measure Type Secondary
Measure Title OS at Clinical Cutoff Among Those With High HER2 mRNA Levels
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population (High HER2 mRNA Subpopulation).

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 160   165   173 
OS at Clinical Cutoff Among Those With High HER2 mRNA Levels 
[Units: Months]
Median (Full Range)
 NA [1] 
 (50.86 to N/A) 
 65.97 
 (54.54 to 67.98) 
 55.39 [2] 
 (48.23 to N/A) 
[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.

No statistical analysis provided for OS at Clinical Cutoff Among Those With High HER2 mRNA Levels



38.  Secondary:   Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With Low HER2 mRNA Levels   [ 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) ]

Measure Type Secondary
Measure Title Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With Low HER2 mRNA Levels
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population (Low HER2 mRNA Subpopulation).

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 170   174   157 
Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With Low HER2 mRNA Levels 
[Units: Percentage of participants]
 51.8   52.9   45.2 

No statistical analysis provided for Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With Low HER2 mRNA Levels



39.  Secondary:   OS at Clinical Cutoff Among Those With Low HER2 mRNA Levels   [ 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) ]

Measure Type Secondary
Measure Title OS at Clinical Cutoff Among Those With Low HER2 mRNA Levels
Measure 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)  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population (Low HER2 mRNA Subpopulation).

Reporting Groups
  Description
Trastuzumab + Taxane 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.
Trastuzumab Emtansine + Placebo 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.
Trastuzumab Emtansine + Pertuzumab 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.

Measured Values
   Trastuzumab + Taxane   Trastuzumab Emtansine + Placebo   Trastuzumab Emtansine + Pertuzumab 
Participants Analyzed 
[Units: Participants]
 170   174   157 
OS at Clinical Cutoff Among Those With Low HER2 mRNA Levels 
[Units: Months]
Median (Full Range)
 43.96 
 (37.19 to 54.87) 
 47.84 
 (42.09 to 53.85) 
 53.29 [1] 
 (46.75 to N/A) 
[1] Upper limit of CI was not reached due to low number of participants with events.

No statistical analysis provided for OS at Clinical Cutoff Among Those With Low HER2 mRNA Levels




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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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 agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Medical Communications
Organization: Hoffmann-La Roche
phone: 800-821-8590
e-mail: genentech@druginfo.com


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

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