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

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Breast Cancer
Interventions	Drug: docetaxel; Drug: paclitaxel; Drug: pertuzumab; Drug: pertuzumab-placebo; Drug: trastuzumab [Herceptin]; Drug: trastuzumab emtansine
Enrollment	1095

Participant Flow

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Recruitment Details
Pre-assignment Details

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Period Title: Overall Study
Started	365	367	363
Treated	355	365	360
Completed	0	0	0
Not Completed	365	367	363
Reason Not Completed
Adverse Event	0	1	0
Lost to Follow-up	13	13	11
Physician Decision	9	1	3
Reason not Specified	8	3	12
Sponsor Decision to Terminate Study	133	144	143
Subject/ Guardian Decision to Withdraw	32	29	25
Death	170	176	169

Baseline Characteristics

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Arm/Group Title		Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab	Total
Arm/Group Description		Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Total of all reporting groups
Overall Number of Baseline Participants		365	367	363	1095
Baseline Analysis Population Description		Intent-to-Treat (ITT) Population: All participants randomized in the study.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	365 participants	367 participants	363 participants	1095 participants
		54.2 (11.3)	52.6 (11.4)	52.2 (12.0)	53.0 (11.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	365 participants	367 participants	363 participants	1095 participants
	Female	362 99.2%	365 99.5%	361 99.4%	1088 99.4%
	Male	3 0.8%	2 0.5%	2 0.6%	7 0.6%

Outcome Measures

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1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	365	367	363
Measure Type: Number; Unit of Measure: percentage of participants
	63.3	64.3	59.8

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	365	367	363
Median (95% Confidence Interval); Unit of Measure: months
	13.7; (12.4 to 14.9)	14.1; (10.9 to 16.8)	15.2; (12.5 to 18.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The study was powered for superiority with target hazard ratio (HR) equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. Non-inferiority was established if the upper bound of the 97.5% CI was less than (<) 1.1765. Superiority was achieved if the upper bound of the 97.5% CI was <1.00.
Statistical Test of Hypothesis	P-Value	0.3125
	Comments	Test and p-value apply for superiority test. Two-sided significance level of 2.5% was used to adjust for independent comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 97.5%; 0.73 to 1.13
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Placebo vs. Trastuzumab + Taxane

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The study was powered for superiority with target HR equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. Non-inferiority was established if the upper bound of the 97.5% CI was <1.1765. Superiority was achieved if the upper bound of the 97.5% CI was <1.00.
Statistical Test of Hypothesis	P-Value	0.1407
	Comments	Test and p-value apply for superiority test. Two-sided significance level of 2.5% was used to adjust for independent comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 97.5%; 0.69 to 1.08
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs. Trastuzumab + Taxane

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Emtansine + Placebo, Trastuzumab Emtansine + Pertuzumab
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The study was powered for superiority with target HR equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
Statistical Test of Hypothesis	P-Value	0.3075
	Comments	Test and p-value apply for superiority test. Primary endpoint did not meet superiority of PFS for trastuzumab emtansine + pertuzumab versus trastuzumab + taxane (two-sided significance level 2.5%); thus, tests and p-value are considered descriptive.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 97.5%; 0.73 to 1.13
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs. Trastuzumab Emtansine + Placebo

3. Secondary Outcome

Title	Percentage of Participants Who Died Prior to Clinical Cutoff
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)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	365	367	363
Measure Type: Number; Unit of Measure: percentage of participants
	46.3	47.7	46.3

4. Secondary Outcome

Title	Overall Survival (OS) at Clinical Cutoff
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)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	365	367	363
Median (95% Confidence Interval); Unit of Measure: months
	50.86; (44.75 to 60.75)	53.68; (48.36 to 64.36)	51.78 [1]; (47.87 to NA)

[1]

Upper limit of CI was not reached due to low number of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6568
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 97.5%; 0.73 to 1.20
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5691
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 97.5%; 0.67 to 1.11
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	365	367	363
Measure Type: Number; Unit of Measure: percentage of participants
	72.1	70.3	67.5

6. Secondary Outcome

Title	PFS According to Investigator Assessment
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)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	365	367	363
Median (95% Confidence Interval); Unit of Measure: months
	12.5; (10.5 to 13.6)	14.1; (12.2 to 16.7)	14.8; (12.4 to 17.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 97.5%; 0.69 to 1.04
	Estimation Comments	Direction of comparison: Trastuzumab Emtasine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 97.5%; 0.63 to 0.95
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane

7. Secondary Outcome

Title	Percentage of Participants Experiencing Treatment Failure
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

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	365	367	363
Measure Type: Number; Unit of Measure: percentage of participants
	85.8	82.6	80.2

8. Secondary Outcome

Title	Time to Treatment Failure (TTF)
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

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	365	367	363
Median (95% Confidence Interval); Unit of Measure: months
	10.2; (9.2 to 11.8)	12.1; (9.9 to 13.9)	11.8; (9.9 to 14.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 97.5%; 0.66 to 0.97
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 97.5%; 0.65 to 0.95
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane

9. Secondary Outcome

Title	One-Year Survival Rate
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

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	365	367	363
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage probability of being alive
	91.4; (88.44 to 94.41)	92.4; (89.62 to 95.15)	91.9; (89.00 to 94.77)

10. Secondary Outcome

Title	Percentage of Participants With Grade ≥3 Adverse Events
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

Outcome Measure Data

Analysis Population Description

Safety Population: All treated participants. Additionally, 2 participants randomized to trastuzumab+taxane received 3 cycles of trastuzumab emtansine and were included in trastuzumab emtansine+placebo arm. 6 participants randomized to trastuzumab emtansine+placebo received pertuzumab and were included in trastuzumab emtansine+pertuzumab arm.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	353	361	366
Measure Type: Number; Unit of Measure: percentage of participants
	54.1	45.4	46.2

11. Secondary Outcome

Title	Percentage of Participants Who Died at 2 Years
Description	[Not Specified]
Time Frame	From randomization until 2 years

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	365	367	363
Measure Type: Number; Unit of Measure: percentage of participants
	20.3	20.2	19.6

12. Secondary Outcome

Title	Overall Survival Truncated at 2 Years
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

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	365	367	363
Measure Type: Number; Unit of Measure: percentage of participants
	79.7	79.8	80.4

13. Secondary Outcome

Title	Percentage of Participants With Grade 5 Adverse Events
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)

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	353	361	366
Measure Type: Number; Unit of Measure: percentage of participants
	1.7	1.1	1.9

14. Secondary Outcome

Title	Percentage of Participants With Grade 3-4 Laboratory Parameters
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

Outcome Measure Data

Analysis Population Description

Safety population. Number of participants analyzed=participants with available data for the outcome.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	352	361	363
Measure Type: Number; Unit of Measure: percentage of participants
Hemoglobin-Low: Grade 3	4.3	5.8	6.9
Neutrophils-Low: Grade 3	20.2	5.5	5.0
Neutrophils-Low: Grade 4	43.8	1.9	0.8
Platelets-Low: Grade 3	0.9	12.7	12.9
Platelets-Low: Grade 4	0.3	2.8	2.5
Alkaline Phosphate-High: Grade 3	1.1	3.9	3.0
Alanine Transaminase-High: Grade 3	3.4	9.1	8.0
Alanine Transaminase-High: Grade 4	0.0	0.3	0.6
Aspartate Aminotransferase-High: Grade 3	1.1	11.9	6.9
Aspartate Aminotransferase-High: Grade 4	0.0	0.3	0.3
Creatinine-High: Grade 3	0.9	0.3	1.1
Creatinine-High: Grade 4	0.0	0.0	0.3
Potassium-Low: Grade 3	4.3	4.7	5.2
Potassium-Low: Grade 4	0.6	1.7	0.6
Total Bilirubin-High: Grade 3	0.3	0.3	0.3

15. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	353	361	366
Measure Type: Number; Unit of Measure: percentage of participants
	7.6	6.1	7.9

16. Secondary Outcome

Title	Hospitalization Days
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

Outcome Measure Data

Analysis Population Description

Safety population. Number of participants analyzed=participants with hospitalization and data available for calculation of the parameter.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	353	361	366
Median (Full Range); Unit of Measure: days
	6; (1 to 50)	5; (1 to 117)	8; (1 to 381)

17. Secondary Outcome

Title	Percentage of Participants With Hospitalization
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

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	353	361	366
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	21.8; (17.62 to 26.36)	20.2; (16.20 to 24.71)	22.1; (18.03 to 26.70)

18. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with measurable disease at Baseline were included in the analysis.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	287	303	299
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	67.9; (62.26 to 73.31)	59.7; (54.07 to 65.30)	64.2; (58.62 to 69.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Response Rate
	Estimated Value	-8.2
	Confidence Interval	(2-Sided) 95%; -15.9 to -0.5
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Response Rate
	Estimated Value	-3.7
	Confidence Interval	(2-Sided) 95%; -11.4 to 3.9
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Emtansine + Placebo, Trastuzumab Emtansine + Pertuzumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Response Rate
	Estimated Value	4.5
	Confidence Interval	(2-Sided) 95%; -3.3 to 12.2
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab Emtansine + Placebo

19. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	365	367	363
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	69.3; (63.74 to 74.52)	64.6; (59.12 to 69.87)	67.5; (62.17 to 72.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Response Rate
	Estimated Value	-4.6
	Confidence Interval	(2-Sided) 95%; -12.1 to 2.8
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Response Rate
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -9.2 to 5.7
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Emtansine + Placebo, Trastuzumab Emtansine + Pertuzumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Response Rate
	Estimated Value	2.9
	Confidence Interval	(2-Sided) 95%; -4.5 to 10.3
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab Emtansine + Placebo

20. Secondary Outcome

Title	Duration of Response According to IRF Assessment
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)

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants achieving CR or PR were included in the analysis.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	195	181	192
Median (95% Confidence Interval); Unit of Measure: months
	12.5; (10.5 to 16.6)	20.7; (14.8 to 25.0)	21.2; (15.8 to 29.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 97.5%; 0.43 to 0.84
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 97.5%; 0.45 to 0.85
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane

21. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data were not analyzed. Protocol Amendment E removed this outcome measure as a secondary endpoint, because it was redundant to another prespecified secondary endpoint.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

22. Secondary Outcome

Title	Percentage of Participants Experiencing a Clinically Significant Increase in Taxane-Related Treatment Symptoms as Measured by Taxane Subscale of the Functional Assessment of Cancer Therapy (FACT) Taxane (FACT-TaxS) Score
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)

Outcome Measure Data

Analysis Population Description

ITT Population (Protocol Amendment C Subpopulation): All randomized participants who entered the study after Protocol Amendment C.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	173	171	154
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	93.1; (88.48 to 96.06)	60.8; (53.39 to 67.93)	68.8; (61.32 to 75.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Symptom Rate
	Estimated Value	-32.2
	Confidence Interval	(2-Sided) 95%; -40 to -24
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Symptom Rate
	Estimated Value	-24.2
	Confidence Interval	(2-Sided) 95%; -32 to -16
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Emtansine + Placebo, Trastuzumab Emtansine + Pertuzumab
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Symptom Rate
	Estimated Value	8.0
	Confidence Interval	(2-Sided) 95%; -2.3 to 18.4
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab Emtansine + Placebo

23. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population (Protocol Amendment C Subpopulation). Only participants with a FACT-C score at the designated visit (n) were included in the analysis.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	173	171	154
Measure Type: Number; Unit of Measure: percentage of participants
Nausea, Baseline (n=166,166,150)	22.3	14.5	21.3
Nausea, Cycle 1 Day 8 (n=121,114,95)	38.0	36.0	52.6
Nausea, Cycle 2 Day 1 (n=147,151,138)	27.2	20.5	36.2
Nausea, Cycle 2 Day 8 (n=122,121,105)	35.2	28.1	45.7

24. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population (Protocol Amendment C Subpopulation). Only participants with a FACT-C score at the designated visit (n) were included in the analysis.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	173	171	154
Measure Type: Number; Unit of Measure: percentage of participants
Diarrhea, Baseline (n=173,170,153)	15.0	7.6	11.8
Diarrhea, Cycle 1 Day 8 (n=124,117,98)	34.7	17.9	34.7
Diarrhea, Cycle 2 Day 1 (n=161,160,144)	24.2	11.3	39.6
Diarrhea, Cycle 2 Day 8 (n=125,123,107)	34.4	8.1	41.1

25. Secondary Outcome

Title	Percentage of Participants With a Clinically Significant Deterioration in Health Related Quality of Life (HRQoL) as Measured by FACT Breast (FACT-B) Trial Outcome Index-Physical Function Breast (TOI-PFB) Score
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)

Outcome Measure Data

Analysis Population Description

ITT Population. Number of participants analyzed=participants with baseline and at least one post baseline FACT-B TOI-PFB score.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	327	352	338
Measure Type: Number; Unit of Measure: percentage of participants
	61.8	50.9	50.6

26. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population. Number of participants analyzed=participants with baseline and at least one post baseline FACT-B TOI-PFB score.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	327	352	338
Median (95% Confidence Interval); Unit of Measure: months
	3.6; (3.0 to 4.4)	7.7; (6.2 to 11.9)	9.0; (5.1 to 14.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.57 to 0.86
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Pertuzumab
	Comments	Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.55 to 0.84
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane

27. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population. Here, 'n' signifies the number of participants with available data at baseline and Cycle 7 (Week 18).

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	365	367	363
Mean (95% Confidence Interval); Unit of Measure: units on a scale
Baseline (n=344,355,344)	85.0; (82.9 to 87.2)	85.5; (83.3 to 87.8)	85.7; (83.5 to 87.8)
Change From Baseline at Cycle 7 (n=261,252,261)	-1.6; (-4.2 to 1.0)	2.3; (0.4 to 4.2)	-0.2; (-2.1 to 1.6)

28. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Number of participants analysed=participants from ITT population who were employed at baseline. Here, 'n' signifies the number of participants with available data at specified category.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	67	64	67
Mean (95% Confidence Interval); Unit of Measure: percent of work
% Work Time Missed at Baseline (n=66,63,67)	15.3; (9.2 to 21.4)	9.5; (4.2 to 14.8)	13.6; (7.7 to 19.6)
Change in % Work Time Missed (n=35,33,36)	0.4; (-7.3 to 8.2)	-0.0; (-4.5 to 4.5)	-4.3; (-13.0 to 4.6)
% Impairment While Working at Baseline(n=67,64,67)	20.0; (14.1 to 25.9)	15.3; (9.5 to 21.1)	19.9; (13.6 to 26.1)
Change in % Impairment While Working (n=34,32,35)	8.8; (2.0 to 15.6)	-0.3; (-11.0 to 10.5)	-2.7; (-11.0 to 5.2)
% Overall Work Impairment at Baseline (n=65,62,66)	28.5; (20.7 to 36.2)	21.2; (13.8 to 28.7)	28.1; (20.3 to 35.9)
Change in % Overall Work Impairment (n=34,31,35)	9.1; (-0.4 to 18.6)	-1.1; (-13.0 to 11.0)	-4.6; (-14.0 to 5.0)

29. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Number of participants analysed=participants from ITT population who reported conduct of daily activities. Here, 'n' signifies the number of participants with available data at specified category.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	312	334	321
Mean (95% Confidence Interval); Unit of Measure: units on a scale
% Activity Impairment at Baseline (n=312,334,321)	32.9; (29.6 to 36.3)	33.6; (30.2 to 37.0)	32.7; (29.5 to 36.0)
Change in % Activity Impairment (n=227,222,234)	4.5; (0.2 to 8.7)	-5.3; (-9.5 to -1.1)	-3.7; (-7.2 to -0.1)

30. Secondary Outcome

Title	Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With High Human Epidermal Growth Factor Receptor 2 (HER2) Messenger Ribonucleic Acid (mRNA) Levels
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)

Outcome Measure Data

Analysis Population Description

ITT Population (High HER2 mRNA Subpopulation): All randomized participants with above-the-median HER2 mRNA expression (value greater than [>] 59.71). Only participants with measurable disease at Baseline were included in the analysis.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	132	136	147
Measure Type: Number; Unit of Measure: percentage of participants
	75.0	66.9	63.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.40 to 1.15
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

31. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population (Low HER2 mRNA Subpopulation): All randomized participants with below-the-median HER2 mRNA expression (value less than or equal to [≤] 59.71). Only participants with measurable disease at Baseline were included in the analysis.

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	126	147	127
Measure Type: Number; Unit of Measure: percentage of participants
	61.9	51.7	66.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.41 to 1.07
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

32. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population (High HER2 mRNA Subpopulation).

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	160	165	173
Measure Type: Number; Unit of Measure: percentage of participants
	59.4	57.6	56.1

33. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population (High HER2 mRNA Subpopulation).

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	160	165	173
Median (Full Range); Unit of Measure: months
	15.9; (0.1 to 46.4)	18.6; (0.1 to 46.0)	18.7; (0.1 to 48.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 97.5%; 0.65 to 1.25
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

34. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population (Low HER2 mRNA Subpopulation).

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	170	174	157
Measure Type: Number; Unit of Measure: percentage of participants
	66.5	70.1	62.4

35. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population (Low HER2 mRNA Subpopulation).

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	170	174	157
Median (Full Range); Unit of Measure: months
	12.4; (0.1 to 47.3)	10.2; (0.1 to 43.6)	14.5; (0.1 to 40.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab + Taxane, Trastuzumab Emtansine + Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 97.5%; 0.74 to 1.34
	Estimation Comments	Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane

36. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population (High HER2 mRNA Subpopulation).

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	160	165	173
Measure Type: Number; Unit of Measure: percentage of participants
	38.8	41.2	45.1

37. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population (High HER2 mRNA Subpopulation).

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	160	165	173
Median (Full Range); Unit of Measure: months
	NA [1]; (50.86 to NA)	65.97; (54.54 to 67.98)	55.39 [2]; (48.23 to NA)

[1]

Median duration of OS was not reached due to insufficient follow-up. Upper limit of CI was not reached due to low number of participants with events.

[2]

Upper limit of CI was not reached due to low number of participants with events.

38. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population (Low HER2 mRNA Subpopulation).

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	170	174	157
Measure Type: Number; Unit of Measure: percentage of participants
	51.8	52.9	45.2

39. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population (Low HER2 mRNA Subpopulation).

Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description:	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
Overall Number of Participants Analyzed	170	174	157
Median (Full Range); Unit of Measure: months
	43.96; (37.19 to 54.87)	47.84; (42.09 to 53.85)	53.29 [1]; (46.75 to NA)

[1]

Upper limit of CI was not reached due to low number of participants with events.

Adverse Events

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Top of Page Participant Flow Baseline Characteristics Outcome Measures Adverse Events Limitations and Caveats Information More Information

Time Frame	Up to 70 months from randomization until clinical cutoff of 16 September 2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination).
Adverse Event Reporting Description	Safety Population: All randomized participants who received at least one dose of study treatment and the participants were analyzed based on the treatment they actually received (N=353 in Trastuzumab + Taxane arm, N=361 in Trastuzumab Emtansine, Pertuzumab-placebo arm, N=366 in Trastuzumab emtansine + pertuzumab arm).
Arm/Group Title	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
Arm/Group Description	Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.	Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.	Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
All-Cause Mortality
	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	81/353 (22.95%)	86/361 (23.82%)	93/366 (25.41%)
Blood and lymphatic system disorders
Febrile neutropenia * 1	13/353 (3.68%)	0/361 (0.00%)	0/366 (0.00%)
Anaemia * 2	1/353 (0.28%)	5/361 (1.39%)	6/366 (1.64%)
Neutropenia * 2	5/353 (1.42%)	0/361 (0.00%)	0/366 (0.00%)
Thrombocytopenia * 2	0/353 (0.00%)	2/361 (0.55%)	2/366 (0.55%)
Hypercoagulation * 2	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Leukopenia * 2	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Cardiac disorders
Atrial fibrillation * 1	1/353 (0.28%)	0/361 (0.00%)	1/366 (0.27%)
Cardiac failure * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Cardiac failure congestive * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Myocardial infarction * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Pericardial effusion * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Supraventricular tachycardia * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Ventricular tachycardia * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Acute Myocardial Infarction * 2	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Ear and labyrinth disorders
Vertigo * 1	0/353 (0.00%)	0/361 (0.00%)	2/366 (0.55%)
Eye disorders
Blindness transient * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Macular hole * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Ocular hypertension * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Gastrointestinal disorders
Diarrhoea * 1	4/353 (1.13%)	0/361 (0.00%)	0/366 (0.00%)
Vomiting * 1	1/353 (0.28%)	0/361 (0.00%)	4/366 (1.09%)
Abdominal pain * 1	2/353 (0.57%)	1/361 (0.28%)	0/366 (0.00%)
Gastritis * 1	0/353 (0.00%)	0/361 (0.00%)	2/366 (0.55%)
Rectal haemorrhage * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Anal fistula * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Colitis * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Diverticulum * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Gastric haemorrhage * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Gastric ulcer * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Gastritis erosive * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Large intestine perforation * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Lower gastrointestinal haemorrhage * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Mallory-Weiss syndrome * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Mouth haemorrhage * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Nausea * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Splenic artery aneurysm * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Umbilical hernia * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Upper gastrointestinal haemorrhage * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Abdominal Discomfort * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Ascites * 2	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Gastrointestinal Haemorrhage * 2	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Haemorrhoidal Haemorrhage * 2	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
General disorders
Pyrexia * 1	2/353 (0.57%)	4/361 (1.11%)	5/366 (1.37%)
Fatigue * 1	3/353 (0.85%)	1/361 (0.28%)	1/366 (0.27%)
Non-cardiac chest pain * 1	0/353 (0.00%)	2/361 (0.55%)	1/366 (0.27%)
Death * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
General physical health deterioration * 1	0/353 (0.00%)	0/361 (0.00%)	2/366 (0.55%)
Pain * 1	0/353 (0.00%)	0/361 (0.00%)	2/366 (0.55%)
Asthenia * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Catheter site haematoma * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Malaise * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Oedema * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Peripheral swelling * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Adverse Drug Reaction * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Sudden Death * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Hepatobiliary disorders
Cholecystitis * 1	0/353 (0.00%)	1/361 (0.28%)	1/366 (0.27%)
Hepatic Fibrosis * 2	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Hepatic Haematoma * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Immune system disorders
Hypersensitivity * 1	0/353 (0.00%)	2/361 (0.55%)	2/366 (0.55%)
Anaphylactic reaction * 1	2/353 (0.57%)	0/361 (0.00%)	1/366 (0.27%)
Cytokine release syndrome * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Anaphylactic Shock * 2	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Anaphylactoid Reaction * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Infections and infestations
Pneumonia * 1	4/353 (1.13%)	3/361 (0.83%)	5/366 (1.37%)
Cellulitis * 1	3/353 (0.85%)	3/361 (0.83%)	1/366 (0.27%)
Sepsis * 1	1/353 (0.28%)	0/361 (0.00%)	4/366 (1.09%)
Device related infection * 1	0/353 (0.00%)	1/361 (0.28%)	1/366 (0.27%)
Gastroenteritis * 1	1/353 (0.28%)	0/361 (0.00%)	2/366 (0.55%)
Infection * 1	1/353 (0.28%)	1/361 (0.28%)	1/366 (0.27%)
Neutropenic sepsis * 1	3/353 (0.85%)	0/361 (0.00%)	0/366 (0.00%)
Septic shock * 1	2/353 (0.57%)	1/361 (0.28%)	1/366 (0.27%)
Bronchitis * 1	0/353 (0.00%)	0/361 (0.00%)	3/366 (0.82%)
Herpes zoster * 1	2/353 (0.57%)	0/361 (0.00%)	0/366 (0.00%)
Upper respiratory tract infection * 1	1/353 (0.28%)	1/361 (0.28%)	0/366 (0.00%)
Urinary tract infection * 1	2/353 (0.57%)	0/361 (0.00%)	0/366 (0.00%)
Wound infection * 1	1/353 (0.28%)	1/361 (0.28%)	0/366 (0.00%)
Arthritis infective * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Atypical pneumonia * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Breast abscess * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Chorioretinitis * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Clostridium difficile colitis * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Clostridium difficile infection * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Cystitis * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Empyema * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Erysipelas * 1	1/353 (0.28%)	1/361 (0.28%)	0/366 (0.00%)
Escherichia sepsis * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Gastroenteritis viral * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Influenza * 1	1/353 (0.28%)	1/361 (0.28%)	0/366 (0.00%)
Klebsiella sepsis * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Localised infection * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Lower respiratory tract infection * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Lung infection * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Mastitis * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Nasopharyngitis * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Pneumonia pneumococcal * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Rectal abscess * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Respiratory tract infection * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Streptococcal sepsis * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Tooth infection * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Urosepsis * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Abscess Limb * 2	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Appendicitis Perforated * 2	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Catheter Site Infection * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Skin Infection * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Injury, poisoning and procedural complications
Infusion related reaction * 1	1/353 (0.28%)	7/361 (1.94%)	13/366 (3.55%)
Femur fracture * 1	1/353 (0.28%)	0/361 (0.00%)	3/366 (0.82%)
Pubis fracture * 1	1/353 (0.28%)	0/361 (0.00%)	1/366 (0.27%)
Arterial injury * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Contusion * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Fall * 1	0/353 (0.00%)	2/361 (0.55%)	0/366 (0.00%)
Femoral neck fracture * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Gastrointestinal stoma complication * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Hip fracture * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Radiation retinopathy * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Spinal compression fracture * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Subdural haematoma * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Wound secretion * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Abdominal Injury * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Foot Fracture * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Fracture * 2	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Stomal Hernia * 2	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Uncoded serious adverse event * 2 [1]	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Investigations
Alanine aminotransferase increased * 1	0/353 (0.00%)	0/361 (0.00%)	2/366 (0.55%)
Aspartate aminotransferase increased * 1	0/353 (0.00%)	0/361 (0.00%)	2/366 (0.55%)
Body temperature increased * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
International normalised ratio increased * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Oxygen saturation decreased * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Metabolism and nutrition disorders
Dehydration * 1	1/353 (0.28%)	0/361 (0.00%)	1/366 (0.27%)
Hyperglycaemia * 1	0/353 (0.00%)	2/361 (0.55%)	0/366 (0.00%)
Decreased appetite * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Diabetic ketoacidosis * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Hypercalcaemia * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Hypokalaemia * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Hyponatraemia * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Diabetes Mellitus * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	1/353 (0.28%)	2/361 (0.55%)	1/366 (0.27%)
Back pain * 1	1/353 (0.28%)	1/361 (0.28%)	1/366 (0.27%)
Bone pain * 1	2/353 (0.57%)	1/361 (0.28%)	0/366 (0.00%)
Intervertebral disc protrusion * 1	1/353 (0.28%)	1/361 (0.28%)	0/366 (0.00%)
Exostosis * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Musculoskeletal chest pain * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Musculoskeletal pain * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Neck pain * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Pain in extremity * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Pathological fracture * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Rotator cuff syndrome * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Tenosynovitis * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Breast neoplasm * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Chronic myeloid leukaemia * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Colon neoplasm * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Lung adenocarcinoma * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Myelodysplastic syndrome * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Squamous cell carcinoma of the cervix * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Tumour haemorrhage * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Uterine leiomyoma * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Basal Cell Carcinoma * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Intracranial Tumour Haemorrhage * 2	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Nervous system disorders
Headache * 1	0/353 (0.00%)	2/361 (0.55%)	2/366 (0.55%)
Syncope * 1	0/353 (0.00%)	2/361 (0.55%)	1/366 (0.27%)
Haemorrhage intracranial * 1	1/353 (0.28%)	1/361 (0.28%)	0/366 (0.00%)
Cerebrovascular accident * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Cognitive disorder * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Depressed level of consciousness * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Guillain-Barre syndrome * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Lacunar infarction * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Paraparesis * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Peripheral sensory neuropathy * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Presyncope * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Somnolence * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Vascular dementia * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Cerebral Haemorrhage * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Epilepsy * 2	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Neuropathy Peripheral * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Sciatica * 2	1/353 (0.28%)	0/361 (0.00%)	1/366 (0.27%)
Seizure * 2	1/353 (0.28%)	1/361 (0.28%)	1/366 (0.27%)
Product Issues
Device Breakage * 2	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Psychiatric disorders
Confusional state * 1	0/353 (0.00%)	0/361 (0.00%)	2/366 (0.55%)
Depression * 1	0/353 (0.00%)	1/361 (0.28%)	2/366 (0.55%)
Anxiety * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Mental Status Changes * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Suicide Attempt * 2	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Renal and urinary disorders
Calculus urinary * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Reproductive system and breast disorders
Menorrhagia * 1	0/353 (0.00%)	1/361 (0.28%)	1/366 (0.27%)
Endometrial hypertrophy * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Vaginal haemorrhage * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion * 1	3/353 (0.85%)	1/361 (0.28%)	3/366 (0.82%)
Pulmonary embolism * 1	4/353 (1.13%)	2/361 (0.55%)	1/366 (0.27%)
Dyspnoea * 1	2/353 (0.57%)	1/361 (0.28%)	1/366 (0.27%)
Epistaxis * 1	0/353 (0.00%)	1/361 (0.28%)	3/366 (0.82%)
Interstitial lung disease * 1	1/353 (0.28%)	1/361 (0.28%)	1/366 (0.27%)
Pneumothorax * 1	0/353 (0.00%)	0/361 (0.00%)	2/366 (0.55%)
Acute respiratory failure * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Alveolitis allergic * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Chronic obstructive pulmonary disease * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Hypoxia * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Nasal turbinate hypertrophy * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Pneumonitis * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Pulmonary fibrosis * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Respiratory failure * 1	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Acute Pulmonary Oedema * 2	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
Skin and subcutaneous tissue disorders
Rash * 1	0/353 (0.00%)	2/361 (0.55%)	0/366 (0.00%)
Dermatomyositis * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Peau d’orange * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Cutaneous Lupus Erythematosus * 2	0/353 (0.00%)	1/361 (0.28%)	1/366 (0.27%)
Vascular disorders
Hypertension * 1	1/353 (0.28%)	1/361 (0.28%)	0/366 (0.00%)
Haematoma * 1	0/353 (0.00%)	2/361 (0.55%)	0/366 (0.00%)
Haemorrhage * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Hypertensive crisis * 1	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Hypotension * 1	1/353 (0.28%)	0/361 (0.00%)	0/366 (0.00%)
Aneurysm * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Hypovolaemic Shock * 2	0/353 (0.00%)	0/361 (0.00%)	1/366 (0.27%)
Orthostatic Hypotension * 2	0/353 (0.00%)	1/361 (0.28%)	0/366 (0.00%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (17.1); 2 Term from vocabulary, MedDRA (19.0); [1] Per investigator, this serious adverse event was, "gamma nail implant broke (status after femur fracture)."
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Trastuzumab + Taxane	Trastuzumab Emtansine + Placebo	Trastuzumab Emtansine + Pertuzumab
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	342/353 (96.88%)	352/361 (97.51%)	352/366 (96.17%)
Blood and lymphatic system disorders
Neutropenia * 1	74/353 (20.96%)	44/361 (12.19%)	37/366 (10.11%)
Anaemia * 1	39/353 (11.05%)	48/361 (13.30%)	59/366 (16.12%)
Thrombocytopenia * 1	0/353 (0.00%)	52/361 (14.40%)	61/366 (16.67%)
Ear and labyrinth disorders
Vertigo * 2	11/353 (3.12%)	17/361 (4.71%)	21/366 (5.74%)
Eye disorders
Lacrimation increased * 1	48/353 (13.60%)	13/361 (3.60%)	19/366 (5.19%)
Dry eye * 1	13/353 (3.68%)	25/361 (6.93%)	24/366 (6.56%)
Vision Blurred † 2	10/353 (2.83%)	13/361 (3.60%)	19/366 (5.19%)
Gastrointestinal disorders
Nausea * 1	131/353 (37.11%)	174/361 (48.20%)	192/366 (52.46%)
Diarrhoea * 2	173/353 (49.01%)	92/361 (25.48%)	178/366 (48.63%)
Vomiting * 1	69/353 (19.55%)	80/361 (22.16%)	111/366 (30.33%)
Constipation * 1	72/353 (20.40%)	82/361 (22.71%)	71/366 (19.40%)
Stomatitis * 1	57/353 (16.15%)	37/361 (10.25%)	42/366 (11.48%)
Dyspepsia * 1	38/353 (10.76%)	33/361 (9.14%)	48/366 (13.11%)
Abdominal pain upper * 1	31/353 (8.78%)	39/361 (10.80%)	46/366 (12.57%)
Dry mouth * 1	13/353 (3.68%)	52/361 (14.40%)	45/366 (12.30%)
Abdominal pain * 1	31/353 (8.78%)	35/361 (9.70%)	41/366 (11.20%)
Gingival bleeding * 1	4/353 (1.13%)	31/361 (8.59%)	25/366 (6.83%)
Haemorrhoids * 1	9/353 (2.55%)	12/361 (3.32%)	22/366 (6.01%)
General disorders
Fatigue * 2	128/353 (36.26%)	120/361 (33.24%)	130/366 (35.52%)
Pyrexia * 1	59/353 (16.71%)	96/361 (26.59%)	118/366 (32.24%)
Asthenia * 1	57/353 (16.15%)	62/361 (17.17%)	63/366 (17.21%)
Chills * 1	14/353 (3.97%)	55/361 (15.24%)	97/366 (26.50%)
Oedema peripheral * 1	98/353 (27.76%)	37/361 (10.25%)	35/366 (9.56%)
Mucosal inflammation * 1	40/353 (11.33%)	29/361 (8.03%)	36/366 (9.84%)
Influenza like illness * 1	17/353 (4.82%)	31/361 (8.59%)	32/366 (8.74%)
Non-cardiac chest pain * 1	24/353 (6.80%)	25/361 (6.93%)	27/366 (7.38%)
Pain * 1	29/353 (8.22%)	26/361 (7.20%)	19/366 (5.19%)
Oedema * 1	31/353 (8.78%)	11/361 (3.05%)	3/366 (0.82%)
Infections and infestations
Upper respiratory tract infection * 1	55/353 (15.58%)	50/361 (13.85%)	66/366 (18.03%)
Nasopharyngitis * 1	49/353 (13.88%)	52/361 (14.40%)	66/366 (18.03%)
Urinary tract infection * 1	29/353 (8.22%)	31/361 (8.59%)	41/366 (11.20%)
Rhinitis * 1	18/353 (5.10%)	25/361 (6.93%)	24/366 (6.56%)
Influenza * 1	14/353 (3.97%)	22/361 (6.09%)	25/366 (6.83%)
Paronychia * 1	22/353 (6.23%)	8/361 (2.22%)	30/366 (8.20%)
Pharyngitis * 1	14/353 (3.97%)	19/361 (5.26%)	17/366 (4.64%)
Conjunctivitis * 1	21/353 (5.95%)	14/361 (3.88%)	17/366 (4.64%)
Bronchitis † 2	14/353 (3.97%)	9/361 (2.49%)	20/366 (5.46%)
Investigations
Aspartate aminotransferase increased * 1	9/353 (2.55%)	54/361 (14.96%)	28/366 (7.65%)
Alanine aminotranseferase increased * 1	10/353 (2.83%)	41/361 (11.36%)	35/366 (9.56%)
Weight decreased * 1	7/353 (1.98%)	24/361 (6.65%)	30/366 (8.20%)
Ejection fraction decreased * 1	31/353 (8.78%)	7/361 (1.94%)	16/366 (4.37%)
Gamma- glutamyltranseferase increased * 1	1/353 (0.28%)	30/361 (8.31%)	17/366 (4.64%)
Metabolism and nutrition disorders
Decreased appetite * 1	76/353 (21.53%)	84/361 (23.27%)	84/366 (22.95%)
Hypokalaemia * 1	15/353 (4.25%)	19/361 (5.26%)	30/366 (8.20%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	91/353 (25.78%)	83/361 (22.99%)	71/366 (19.40%)
Myalgia * 1	82/353 (23.23%)	66/361 (18.28%)	61/366 (16.67%)
Back pain * 1	46/353 (13.03%)	60/361 (16.62%)	63/366 (17.21%)
Pain in extremity * 1	48/353 (13.60%)	53/361 (14.68%)	54/366 (14.75%)
Muscle spasms * 1	15/353 (4.25%)	32/361 (8.86%)	62/366 (16.94%)
Musculoskeletal pain * 1	23/353 (6.52%)	30/361 (8.31%)	37/366 (10.11%)
Bone pain * 1	33/353 (9.35%)	17/361 (4.71%)	29/366 (7.92%)
Musculoskeletal chest pain * 1	17/353 (4.82%)	13/361 (3.60%)	20/366 (5.46%)
Neck Pain * 1	12/353 (3.40%)	12/361 (3.32%)	24/366 (6.56%)
Nervous system disorders
Headache * 1	80/353 (22.66%)	116/361 (32.13%)	120/366 (32.79%)
Neuropathy peripheral * 1	99/353 (28.05%)	52/361 (14.40%)	69/366 (18.85%)
Peripheral sensory neuropathy * 1	70/353 (19.83%)	47/361 (13.02%)	46/366 (12.57%)
Dysgeusia * 1	54/353 (15.30%)	30/361 (8.31%)	50/366 (13.66%)
Paraesthesia * 1	41/353 (11.61%)	31/361 (8.59%)	43/366 (11.75%)
Dizziness * 1	35/353 (9.92%)	38/361 (10.53%)	38/366 (10.38%)
Psychiatric disorders
Insomnia * 1	51/353 (14.45%)	51/361 (14.13%)	52/366 (14.21%)
Anxiety * 1	22/353 (6.23%)	26/361 (7.20%)	33/366 (9.02%)
Depression * 1	17/353 (4.82%)	34/361 (9.42%)	20/366 (5.46%)
Reproductive system and breast disorders
Breast pain * 1	18/353 (5.10%)	13/361 (3.60%)	16/366 (4.37%)
Respiratory, thoracic and mediastinal disorders
Epistaxis * 1	53/353 (15.01%)	113/361 (31.30%)	127/366 (34.70%)
Cough * 1	74/353 (20.96%)	72/361 (19.94%)	79/366 (21.58%)
Dyspnoea * 1	56/353 (15.86%)	42/361 (11.63%)	53/366 (14.48%)
Oropharyngeal pain * 1	29/353 (8.22%)	31/361 (8.59%)	30/366 (8.20%)
Rhinorrhoea * 1	26/353 (7.37%)	21/361 (5.82%)	32/366 (8.74%)
Skin and subcutaneous tissue disorders
Alopecia * 1	212/353 (60.06%)	26/361 (7.20%)	33/366 (9.02%)
Rash * 1	86/353 (24.36%)	62/361 (17.17%)	89/366 (24.32%)
Pruritus * 1	32/353 (9.07%)	28/361 (7.76%)	51/366 (13.93%)
Nail disorder * 1	39/353 (11.05%)	11/361 (3.05%)	19/366 (5.19%)
Dry skin * 1	24/353 (6.80%)	24/361 (6.65%)	29/366 (7.92%)
Erythema * 1	24/353 (6.80%)	13/361 (3.60%)	20/366 (5.46%)
Dermatitis acneiform * 1	6/353 (1.70%)	16/361 (4.43%)	27/366 (7.38%)
Palmar-plantar erythrodysaesthesia syndrome * 1	26/353 (7.37%)	6/361 (1.66%)	11/366 (3.01%)
Nail discolouration * 1	25/353 (7.08%)	5/361 (1.39%)	1/366 (0.27%)
Onychoclasis * 2	13/353 (3.68%)	19/361 (5.26%)	17/366 (4.64%)
Vascular disorders
Hypertension * 1	19/353 (5.38%)	37/361 (10.25%)	43/366 (11.75%)
Hot flush * 1	27/353 (7.65%)	16/361 (4.43%)	12/366 (3.28%)
Lymphoedema * 1	27/353 (7.65%)	7/361 (1.94%)	8/366 (2.19%)
† Indicates events were collected by systematic assessment; * Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (17.1); 2 Term from vocabulary, MedDRA (19.0)

Limitations and Caveats

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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 Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

Name/Title: Medical Communications

Organization: Hoffmann-La Roche

Phone: 800-821-8590

EMail: genentech@druginfo.com

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

Bighin C, Pronzato P, Del Mastro L. Trastuzumab emtansine in the treatment of HER-2-positive metastatic breast cancer patients. Future Oncol. 2013 Jul;9(7):955-7. doi: 10.2217/fon.13.74.

Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012 Mar 22;12(4):278-87. doi: 10.1038/nrc3236. Review.

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