Trial Outcomes & Findings for A Study to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel Versus Placebo + Trastuzumab + Docetaxel in Previously Untreated Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Breast Cancer (NCT NCT02896855)

NCT ID: NCT02896855

Last Updated: 2021-12-16

Results Overview

Progression-free survival (PFS) was defined as the time from randomization to first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, PD is defined as a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeters (mm), and the appearance of new lesions. The Kaplan-Meier approach was used to estimate median PFS for each treatment arm. Data for participants who did not have a PFS event were censored at the time of the last tumor assessment (if no tumor assessments performed after baseline, at randomization plus 1 day).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 243 participants
• Primary outcome timeframe: From date of randomization until date of PFS event (Median [range] time on study for Arm A vs. Arm B at Primary analysis: 57.14 [3.3-93.3] weeks vs. 59.64 [0.9-90.4] weeks; Final analysis: 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks)
• Results posted on: 2021-12-16

Participant Flow

Participant milestones

Measure	Arm A: Placebo + Trastuzumab + Docetaxel Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Overall Study STARTED	121	122
Overall Study Received Any Study Treatment	120	122
Overall Study Crossed Over From Placebo to Receive Pertuzumab	12	0
Overall Study COMPLETED	49	69
Overall Study NOT COMPLETED	72	53

Reasons for withdrawal

Measure	Arm A: Placebo + Trastuzumab + Docetaxel Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Overall Study Death	50	40
Overall Study Lost to Follow-up	15	9
Overall Study Withdrawal by Subject	7	4

Baseline Characteristics

A Study to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel Versus Placebo + Trastuzumab + Docetaxel in Previously Untreated Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Breast Cancer

Baseline characteristics by cohort

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=121 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Total n=243 Participants Total of all reporting groups
Age, Continuous	51.3 years STANDARD_DEVIATION 11.2 • n=5 Participants	50.7 years STANDARD_DEVIATION 10.6 • n=7 Participants	51.0 years STANDARD_DEVIATION 10.9 • n=5 Participants
Sex: Female, Male Female	121 Participants n=5 Participants	122 Participants n=7 Participants	243 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Asian	121 Participants n=5 Participants	122 Participants n=7 Participants	243 Participants n=5 Participants
Disease Type: Visceral or Non-Visceral Disease Visceral Disease	86 Participants n=5 Participants	88 Participants n=7 Participants	174 Participants n=5 Participants
Disease Type: Visceral or Non-Visceral Disease Non-Visceral Disease	35 Participants n=5 Participants	34 Participants n=7 Participants	69 Participants n=5 Participants
Hormone Receptor Status Estrogen and Progesterone Receptor Negative	48 Participants n=5 Participants	53 Participants n=7 Participants	101 Participants n=5 Participants
Hormone Receptor Status Estrogen and/or Progesterone Receptor Positive	73 Participants n=5 Participants	69 Participants n=7 Participants	142 Participants n=5 Participants
Measurable or Non-Measurable Disease, According to RECIST v1.1 Measurable Disease	97 Participants n=5 Participants	105 Participants n=7 Participants	202 Participants n=5 Participants
Measurable or Non-Measurable Disease, According to RECIST v1.1 Non-Measurable Disease	24 Participants n=5 Participants	17 Participants n=7 Participants	41 Participants n=5 Participants

PRIMARY outcome

Timeframe: From date of randomization until date of PFS event (Median [range] time on study for Arm A vs. Arm B at Primary analysis: 57.14 [3.3-93.3] weeks vs. 59.64 [0.9-90.4] weeks; Final analysis: 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks)

Population: Intent-to-Treat (ITT) population: consists of all randomized participants, regardless of whether they received any study treatment. Participants are grouped according to the treatment group to which they were randomized.

Progression-free survival (PFS) was defined as the time from randomization to first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, PD is defined as a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeters (mm), and the appearance of new lesions. The Kaplan-Meier approach was used to estimate median PFS for each treatment arm. Data for participants who did not have a PFS event were censored at the time of the last tumor assessment (if no tumor assessments performed after baseline, at randomization plus 1 day).

Outcome measures

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=121 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Progression-Free Survival, as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Primary Analysis	12.4 months Interval 10.4 to 12.7	14.5 months Interval 12.5 to 18.6	—
Progression-Free Survival, as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Final Analysis	12.5 months Interval 10.4 to 14.6	16.5 months Interval 12.7 to 20.2	—

PRIMARY outcome

Timeframe: At 1, 2, and 3 years

Population: ITT population: consists of all randomized participants, regardless of whether they received any study treatment. Participants are grouped according to the treatment group to which they were randomized. The number analyzed per timepoint represents the number of participants remaining at risk for a PFS event at that timepoint.

Progression-free survival (PFS) was defined as the time from randomization to first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, PD is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm, and the appearance of new lesions. The Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for PFS at 1, 2, and 3 years. Data for participants who did not have a PFS event were censored at the time of the last tumor assessment (if no tumor assessments performed after baseline visit, at randomization plus 1 day). At final analysis, the median [range] time on study for Arm A vs. Arm B was 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks.

Outcome measures

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=121 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Progression-Free Survival at 1 to 3 Years, as Determined by the Investigator Using RECIST v1.1 1 Year	52.90 estimate of percentage of participants Interval 43.75 to 62.04	66.37 estimate of percentage of participants Interval 57.86 to 74.87	—
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Progression-Free Survival at 1 to 3 Years, as Determined by the Investigator Using RECIST v1.1 2 Years	19.19 estimate of percentage of participants Interval 11.85 to 26.53	37.85 estimate of percentage of participants Interval 29.03 to 46.66	—
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Progression-Free Survival at 1 to 3 Years, as Determined by the Investigator Using RECIST v1.1 3 Years	12.73 estimate of percentage of participants Interval 6.48 to 18.97	29.44 estimate of percentage of participants Interval 21.04 to 37.84	—

SECONDARY outcome

Timeframe: From date of randomization until the date of death from any cause (Median [range] time on study for Arm A vs. Arm B at Final analysis: 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks)

Population: ITT population: consists of all randomized participants, regardless of whether they received any study treatment. Participants are grouped according to the treatment group to which they were randomized.

Overall survival (OS) was defined as the time from randomization to death from any cause. The Kaplan-Meier approach was used to estimate median OS for each treatment arm. Participants who were alive or lost to follow-up at the time of the analysis were censored at the date they were last known to be alive. Participants with no post-baseline information were censored at the time of randomization plus 1 day. The results reported here are from the final analysis. At the primary completion date, the median duration of OS had not been reached and OS data was not considered mature due to the few number of events reported.

Outcome measures

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=121 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Overall Survival	NA months Interval 22.1 to The median duration of OS and the upper limit of the interquartile range were not estimable because too few events occurred during the study.	NA months Interval 30.6 to The median duration of OS and the upper limit of the interquartile range were not estimable because too few events occurred during the study.	—

SECONDARY outcome

Timeframe: At 1, 2, and 3 Years

Population: ITT population: consists of all randomized participants, regardless of whether they received any study treatment. Participants are grouped according to the treatment group to which they were randomized. The number analyzed per timepoint represents the number of participants remaining at risk for an OS event at that timepoint.

Overall survival (OS) was defined as the time from randomization to death from any cause. The Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for OS (i.e., alive) at 1, 2, and 3 years. Participants who were alive or lost to follow-up at the time of the analysis were censored at the date they were last known to be alive. Participants with no post-baseline information were censored at the time of randomization plus 1 day. At final analysis, the median [range] time on study for Arm A vs. Arm B was 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks.

Outcome measures

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=121 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival at 1 to 3 Years 1 Year	90.64 estimate of percentage of participants Interval 85.37 to 95.91	93.44 estimate of percentage of participants Interval 89.05 to 97.84	—
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival at 1 to 3 Years 2 Years	73.85 estimate of percentage of participants Interval 65.8 to 81.91	78.87 estimate of percentage of participants Interval 71.5 to 86.24	—
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival at 1 to 3 Years 3 Years	58.41 estimate of percentage of participants Interval 49.12 to 67.69	70.79 estimate of percentage of participants Interval 62.5 to 79.09	—

SECONDARY outcome

Timeframe: At Baseline and every 9 weeks from date of randomization until disease progression or death, whichever occurs first (Median [range] time on study for Arm A vs. Arm B at Primary analysis: 57.14 [3.3-93.3] weeks vs. 59.64 [0.9-90.4] weeks)

Population: ITT population: consists of all randomized participants, regardless of whether they received any study treatment. Participants are grouped according to the treatment group to which they were randomized. Only participants with measurable disease at baseline were included in the analysis.

An objective response was defined as a complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1. As per RECIST v1.1, CR is defined as the disappearance of all target lesions, and PR is defined as at least a 30% decrease in the sum of diameters of target lesions. Also per RECIST v1.1, stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum on study; PD is defined as a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm, and the appearance of new lesions. The same assessment technique must be used throughout the study for evaluating a particular lesion, and the same investigator should assess all tumor responses for each participant. Participants without a post-baseline tumor assessment were considered non-responders.

Outcome measures

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=97 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=105 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Percentage of Participants With Measurable Disease at Baseline Who Achieved an Objective Response (Complete or Partial Response), as Determined by the Investigator Using RECIST v1.1 Objective Response (CR + PR)	69.1 percentage of participants Interval 58.88 to 78.07	79.0 percentage of participants Interval 70.01 to 86.38	—
Percentage of Participants With Measurable Disease at Baseline Who Achieved an Objective Response (Complete or Partial Response), as Determined by the Investigator Using RECIST v1.1 Complete Response (CR)	8.2 percentage of participants Interval 3.63 to 15.61	5.7 percentage of participants Interval 2.13 to 12.02	—
Percentage of Participants With Measurable Disease at Baseline Who Achieved an Objective Response (Complete or Partial Response), as Determined by the Investigator Using RECIST v1.1 Partial Response (PR)	60.8 percentage of participants Interval 50.39 to 70.58	73.3 percentage of participants Interval 63.81 to 81.49	—
Percentage of Participants With Measurable Disease at Baseline Who Achieved an Objective Response (Complete or Partial Response), as Determined by the Investigator Using RECIST v1.1 Stable Disease (SD)	20.6 percentage of participants Interval 13.07 to 30.03	15.2 percentage of participants Interval 8.97 to 23.56	—
Percentage of Participants With Measurable Disease at Baseline Who Achieved an Objective Response (Complete or Partial Response), as Determined by the Investigator Using RECIST v1.1 Progressive Disease (PD)	4.1 percentage of participants Interval 1.13 to 10.22	3.8 percentage of participants Interval 1.05 to 9.47	—
Percentage of Participants With Measurable Disease at Baseline Who Achieved an Objective Response (Complete or Partial Response), as Determined by the Investigator Using RECIST v1.1 Missing or Unevaluable	6.2 percentage of participants 95% confidence intervals were only calculated for responses.	1.9 percentage of participants 95% confidence intervals were only calculated for responses.	—

SECONDARY outcome

Timeframe: From date of first occurrence of documented objective response to date of event (Median [range] time on study for Arm A vs. Arm B at Primary analysis: 57.14 [3.3-93.3] weeks vs. 59.64 [0.9-90.4] weeks)

Population: ITT population: consists of all randomized participants, regardless of whether they received any study treatment. Participants are grouped according to the treatment group to which they were randomized. Only participants with measurable disease at baseline who achieved an objective response during the study were included in the analysis.

Duration of objective response was defined as the time from the first occurrence of a documented objective response (complete response [CR] or partial response [PR]) to the time of disease progression, as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, CR is defined as the disappearance of all target lesions, and PR is defined as at least a 30% decrease in the sum of diameters of target lesions. The Kaplan-Meier approach was used to estimate median duration of objective response. Data for participants who did not have an event were censored at the time of the last tumor assessment (if no tumor assessments were performed after baseline visit, at randomization plus 1 day).

Outcome measures

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=67 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=83 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Duration of Objective Response, as Determined by the Investigator Using RECIST v1.1	10.4 months Interval 8.3 to 15.4	12.4 months Interval 10.6 to 14.9	—

SECONDARY outcome

Timeframe: From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)

Population: Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Following approval of Protocol version 4 (07-March-2020), 12 Arm A participants who were receiving placebo crossed over to receive open-label treatment with pertuzumab.

The number of participants per treatment arm experiencing at least one adverse event, including all non-serious and serious adverse events, is reported here. Adverse events reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for participants in Arm A who crossed over from placebo to pertuzumab. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.

Outcome measures

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=120 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel n=12 Participants Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Number of Participants With at Least One Adverse Event	115 Participants	121 Participants	5 Participants

SECONDARY outcome

Timeframe: From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)

Population: Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Following approval of Protocol version 4 (07-March-2020), 12 Arm A participants who were receiving placebo crossed over to receive open-label treatment with pertuzumab.

Adverse event (AE) severity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0); if the AE was not specifically listed, the following grades of severity were used: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening or disabling; and Grade 5 = death. Severe and serious are not synonymous. Severity refers to the intensity of an AE, whereas a serious AE must meet criteria set out in the protocol; both were independently assessed for each AE. AEs reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for participants in Arm A who crossed over from placebo to pertuzumab. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.

Outcome measures

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=120 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel n=12 Participants Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Number of Participants With at Least One Grade ≥3 Adverse Event	83 Participants	90 Participants	1 Participants

SECONDARY outcome

Timeframe: From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)

Population: Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Following approval of Protocol version 4 (07-March-2020), 12 Arm A participants who were receiving placebo crossed over to receive open-label treatment with pertuzumab.

Adverse events reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for participants in Arm A who crossed over from placebo to pertuzumab. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.

Outcome measures

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=120 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel n=12 Participants Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Number of Participants With at Least One Adverse Event Leading to Withdrawal From Any Treatment	10 Participants	15 Participants	0 Participants

SECONDARY outcome

Timeframe: From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)

Population: Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Following approval of Protocol version 4 (07-March-2020), 12 Arm A participants who were receiving placebo crossed over to receive open-label treatment with pertuzumab.

The number of participants with symptomatic left ventricular systolic dysfunction (LVSD) at any time during the study, as determined using echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan, were summarized by treatment arm. Symptomatic LVSD was evaluated according to NCI CTCAE v4.0 (for "heart failure") and the New York Heart Association (NYHA) classification. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.

Outcome measures

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=120 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel n=12 Participants Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Number of Participants With Symptomatic Left Ventricular Systolic Dysfunction (LVSD), as Determined Using Echocardiography (ECHO) or Multiple-Gated Acquisition (MUGA) Scan	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)

Population: Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Following approval of Protocol version 4 (07-March-2020), 12 Arm A participants who were receiving placebo crossed over to receive open-label treatment with pertuzumab.

An asymptomatic decline in LVEF event is reported as an adverse event of "ejection fraction decreased" and is defined as either of the following: an absolute decrease in LVEF of ≥10 percentage points from baseline to an LVEF of <50%; or an asymptomatic decrease in LVEF requiring treatment or leading to discontinuation of pertuzumab (or placebo) and trastuzumab. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.

Outcome measures

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=120 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel n=12 Participants Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Number of Participants With an Asymptomatic Decline in Left Ventricular Ejection Fraction (LVEF) Event, as Determined Using ECHO or MUGA Scan	0 Participants	2 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline, Weeks 9, 18, 27, 36, 45, 54, 63, 72, 81, 90, 99, 108, 117, 126, 135, 144, 153, 162, 171, 180, 189, 198, 207, 216, and 225, Study Drug Discontinuation Visit (up to 4 years, 4 months), and Treatment-Free Follow-Up at 6 months, and 1 and 2 years

Population: Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Number analyzed indicates the number of participants with a baseline LVEF measurement and a post-baseline LVEF measurement at each time point.

Left ventricular ejection fraction (LVEF) is the measurement of how much blood is being pumped out of the left ventricle of the heart with each contraction. LVEF was calculated using the modified Simpson method and must have been ≥55% at baseline as determined by the local facility before a participant could be enrolled in the study. The investigator decided which method of LVEF assessment (ECHO [preferred] or MUGA scan) would be used for each participant at baseline, and the same method was to be used throughout the study, to the extent possible. The LVEF abnormality status categories, as a change relative to LVEF at baseline, included: Increase or no change in LVEF; Decrease of <10 LVEF points; Absolute LVEF value ≥50% and a decrease of ≥10 LVEF points; and Absolute LVEF value <50% and a decrease of ≥10 LVEF points. The overall worst LVEF value was defined as the lowest post-baseline value up to the end of the study, including unscheduled assessments and the post-treatment period.

Outcome measures

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=120 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 9 · Increase or No Change in LVEF	57 Participants	63 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 9 · Decrease <10 LVEF Points	51 Participants	52 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 9 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	3 Participants	4 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 9 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 18 · Increase or No Change in LVEF	61 Participants	62 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 18 · Decrease <10 LVEF Points	33 Participants	45 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 18 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	4 Participants	3 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 18 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	1 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 27 · Increase or No Change in LVEF	54 Participants	51 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 27 · Decrease <10 LVEF Points	35 Participants	43 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 27 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	3 Participants	5 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 27 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 36 · Increase or No Change in LVEF	45 Participants	46 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 36 · Decrease <10 LVEF Points	28 Participants	43 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 36 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	3 Participants	4 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 36 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	1 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 45 · Increase or No Change in LVEF	34 Participants	36 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 45 · Decrease <10 LVEF Points	29 Participants	43 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 45 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	5 Participants	3 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 45 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 54 · Increase or No Change in LVEF	26 Participants	38 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 54 · Decrease <10 LVEF Points	27 Participants	34 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 54 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	4 Participants	3 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 54 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 63 · Increase or No Change in LVEF	21 Participants	30 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 63 · Decrease <10 LVEF Points	17 Participants	33 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 63 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	6 Participants	3 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 63 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 72 · Increase or No Change in LVEF	17 Participants	26 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 72 · Decrease <10 LVEF Points	15 Participants	31 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 72 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	5 Participants	4 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 72 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 81 · Increase or No Change in LVEF	19 Participants	29 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 81 · Decrease <10 LVEF Points	12 Participants	24 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 81 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	3 Participants	2 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 81 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 90 · Increase or No Change in LVEF	17 Participants	24 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 90 · Decrease <10 LVEF Points	11 Participants	20 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 90 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	2 Participants	3 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 90 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 99 · Increase or No Change in LVEF	14 Participants	21 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 99 · Decrease <10 LVEF Points	10 Participants	23 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 99 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	2 Participants	2 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 99 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 108 · Increase or No Change in LVEF	13 Participants	15 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 108 · Decrease <10 LVEF Points	7 Participants	24 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 108 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 Participants	3 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 108 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 117 · Increase or No Change in LVEF	14 Participants	18 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 117 · Decrease <10 LVEF Points	3 Participants	18 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 117 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 Participants	3 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 117 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 126 · Increase or No Change in LVEF	7 Participants	20 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 126 · Decrease <10 LVEF Points	9 Participants	15 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 126 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 Participants	2 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 126 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 135 · Increase or No Change in LVEF	6 Participants	15 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 135 · Decrease <10 LVEF Points	8 Participants	18 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 135 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 Participants	2 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 135 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 144 · Increase or No Change in LVEF	10 Participants	18 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 144 · Decrease <10 LVEF Points	3 Participants	10 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 144 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 Participants	3 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 144 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 153 · Increase or No Change in LVEF	7 Participants	12 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 153 · Decrease <10 LVEF Points	7 Participants	15 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 153 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	0 Participants	3 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 153 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 162 · Increase or No Change in LVEF	7 Participants	17 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 162 · Decrease <10 LVEF Points	6 Participants	12 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 162 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	0 Participants	1 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 162 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 171 · Increase or No Change in LVEF	7 Participants	10 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 171 · Decrease <10 LVEF Points	4 Participants	16 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 171 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 Participants	2 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 171 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 180 · Increase or No Change in LVEF	9 Participants	8 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 180 · Decrease <10 LVEF Points	3 Participants	14 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 180 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	0 Participants	1 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 180 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 189 · Increase or No Change in LVEF	5 Participants	6 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 189 · Decrease <10 LVEF Points	3 Participants	9 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 189 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 189 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 198 · Increase or No Change in LVEF	4 Participants	6 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 198 · Decrease <10 LVEF Points	2 Participants	5 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 198 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 198 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 207 · Increase or No Change in LVEF	2 Participants	5 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 207 · Decrease <10 LVEF Points	1 Participants	3 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 207 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 207 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 216 · Increase or No Change in LVEF	1 Participants	3 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 216 · Decrease <10 LVEF Points	0 Participants	1 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 216 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 216 · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 225 · Increase or No Change in LVEF	—	1 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 225 · Decrease <10 LVEF Points	—	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 225 · Absolute Value ≥50% & Decrease ≥10 LVEF Points	—	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Week 225 · Absolute Value <50% & Decrease ≥10 LVEF Points	—	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Study Drug Discontinuation Visit · Increase or No Change in LVEF	45 Participants	45 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Study Drug Discontinuation Visit · Decrease <10 LVEF Points	28 Participants	39 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Study Drug Discontinuation Visit · Absolute Value ≥50% & Decrease ≥10 LVEF Points	8 Participants	3 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Study Drug Discontinuation Visit · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Treatment-Free Follow-Up at 6 Months · Increase or No Change in LVEF	20 Participants	18 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Treatment-Free Follow-Up at 6 Months · Decrease <10 LVEF Points	20 Participants	18 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Treatment-Free Follow-Up at 6 Months · Absolute Value ≥50% & Decrease ≥10 LVEF Points	3 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Treatment-Free Follow-Up at 6 Months · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Treatment-Free Follow-Up at 1 Year · Increase or No Change in LVEF	13 Participants	4 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Treatment-Free Follow-Up at 1 Year · Decrease <10 LVEF Points	10 Participants	14 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Treatment-Free Follow-Up at 1 Year · Absolute Value ≥50% & Decrease ≥10 LVEF Points	0 Participants	1 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Treatment-Free Follow-Up at 1 Year · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Treatment-Free Follow-Up at 2 Years · Increase or No Change in LVEF	1 Participants	2 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Treatment-Free Follow-Up at 2 Years · Decrease <10 LVEF Points	0 Participants	1 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Treatment-Free Follow-Up at 2 Years · Absolute Value ≥50% & Decrease ≥10 LVEF Points	2 Participants	1 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Treatment-Free Follow-Up at 2 Years · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	0 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Overall Worst LVEF Value (Maximum LVEF Decrease) · Increase or No Change in LVEF	21 Participants	20 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Overall Worst LVEF Value (Maximum LVEF Decrease) · Decrease <10 LVEF Points	75 Participants	75 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Overall Worst LVEF Value (Maximum LVEF Decrease) · Absolute Value ≥50% & Decrease ≥10 LVEF Points	16 Participants	22 Participants	—
Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans Overall Worst LVEF Value (Maximum LVEF Decrease) · Absolute Value <50% & Decrease ≥10 LVEF Points	0 Participants	2 Participants	—

SECONDARY outcome

Timeframe: Baseline and every 9 weeks from date of randomization until treatment discontinuation (up to 4 years, 4 months)

Population: Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Number analyzed indicates participants with a baseline LVEF measurement and at least one post-baseline LVEF measurement, respectively.

The baseline left ventricular ejection fraction (LVEF) and change from baseline to the maximum on-treatment decrease in LVEF at any point during the study are reported here. LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. LVEF was calculated using the modified Simpson method and must have been ≥55% at baseline as determined by the local facility before a participant could be enrolled in the study. The investigator decided which method of LVEF assessment (ECHO [preferred] or MUGA scan) would be used for each participant at baseline, and the same method should have been used throughout the study, to the extent possible. At final analysis, the median [range] time on study for Arm A vs. Arm B was 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks.

Outcome measures

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=120 Participants Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 Participants Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Baseline LVEF and Change From Baseline to Maximum On-Treatment Decrease in LVEF at Any Point During the Study Baseline LVEF (value at visit)	64.23 percentage points of LVEF Standard Deviation 4.90	65.08 percentage points of LVEF Standard Deviation 4.43	—
Baseline LVEF and Change From Baseline to Maximum On-Treatment Decrease in LVEF at Any Point During the Study Change from Baseline to Max Decrease in LVEF	-4.88 percentage points of LVEF Standard Deviation 5.41	-5.48 percentage points of LVEF Standard Deviation 5.06	—

Adverse Events

Arm A: Placebo + Trastuzumab + Docetaxel

Serious events: 23 serious events

Other events: 114 other events

Deaths: 50 deaths

Arm B: Pertuzumab + Trastuzumab + Docetaxel

Serious events: 30 serious events

Other events: 119 other events

Deaths: 40 deaths

Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=120 participants at risk Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 participants at risk Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel n=12 participants at risk Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Blood and lymphatic system disorders Febrile neutropenia	3.3% 4/120 • Number of events 4 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	2.5% 3/122 • Number of events 3 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Blood and lymphatic system disorders Leukopenia	1.7% 2/120 • Number of events 3 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	2.5% 3/122 • Number of events 3 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Blood and lymphatic system disorders Neutropenia	6.7% 8/120 • Number of events 16 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	7.4% 9/122 • Number of events 16 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Cardiac disorders Cardiac tamponade	0.00% 0/120 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	1.6% 2/122 • Number of events 2 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Cardiac disorders Ventricular arrhythmia	0.83% 1/120 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/122 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Gastrointestinal disorders Ascites	0.00% 0/120 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.82% 1/122 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Gastrointestinal disorders Oesophagitis	0.00% 0/120 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.82% 1/122 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
General disorders Death	0.83% 1/120 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.82% 1/122 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Hepatobiliary disorders Liver injury	0.83% 1/120 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/122 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Infections and infestations Pneumonia	2.5% 3/120 • Number of events 3 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	4.1% 5/122 • Number of events 5 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Infections and infestations Upper respiratory tract infection	0.00% 0/120 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.82% 1/122 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Injury, poisoning and procedural complications Fracture	0.83% 1/120 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.82% 1/122 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Investigations Alanine aminotransferase increased	1.7% 2/120 • Number of events 2 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/122 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Investigations Aspartate aminotransferase increased	0.83% 1/120 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/122 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Investigations Blood glucose increased	0.00% 0/120 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.82% 1/122 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Metabolism and nutrition disorders Hyperuricaemia	0.83% 1/120 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/122 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Nervous system disorders Dizziness	0.00% 0/120 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.82% 1/122 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Reproductive system and breast disorders Metrorrhagia	0.83% 1/120 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/122 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Reproductive system and breast disorders Pelvic prolapse	0.00% 0/120 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.82% 1/122 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.83% 1/120 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/122 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Gastrointestinal disorders Large intestine polyp	0.00% 0/120 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/122 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	8.3% 1/12 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Vascular disorders Peripheral arterial occlusive disease	0.00% 0/120 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/122 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	8.3% 1/12 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Infections and infestations Osteomyelitis	0.00% 0/120 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.82% 1/122 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Infections and infestations Soft tissue infection	0.00% 0/120 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.82% 1/122 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastrointestinal carcinoma in situ	0.00% 0/120 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.82% 1/122 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.

Other adverse events

Measure	Arm A: Placebo + Trastuzumab + Docetaxel n=120 participants at risk Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram \[mg/kg\] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter \[mg/m\^2\]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm B: Pertuzumab + Trastuzumab + Docetaxel n=122 participants at risk Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel n=12 participants at risk Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m\^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Blood and lymphatic system disorders Anaemia	48.3% 58/120 • Number of events 112 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	54.9% 67/122 • Number of events 179 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Blood and lymphatic system disorders Leukopenia	72.5% 87/120 • Number of events 319 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	74.6% 91/122 • Number of events 349 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Blood and lymphatic system disorders Neutropenia	67.5% 81/120 • Number of events 305 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	71.3% 87/122 • Number of events 314 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	8.3% 1/12 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Blood and lymphatic system disorders Thrombocytopenia	10.0% 12/120 • Number of events 28 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	7.4% 9/122 • Number of events 25 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Gastrointestinal disorders Abdominal distension	5.0% 6/120 • Number of events 6 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	5.7% 7/122 • Number of events 11 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Gastrointestinal disorders Abdominal pain upper	6.7% 8/120 • Number of events 13 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	6.6% 8/122 • Number of events 9 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Gastrointestinal disorders Constipation	9.2% 11/120 • Number of events 15 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	6.6% 8/122 • Number of events 10 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Gastrointestinal disorders Diarrhoea	23.3% 28/120 • Number of events 57 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	45.9% 56/122 • Number of events 102 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Gastrointestinal disorders Flatulence	3.3% 4/120 • Number of events 5 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	6.6% 8/122 • Number of events 8 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Gastrointestinal disorders Mouth ulceration	5.0% 6/120 • Number of events 7 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	8.2% 10/122 • Number of events 16 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Gastrointestinal disorders Nausea	12.5% 15/120 • Number of events 24 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	12.3% 15/122 • Number of events 28 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Gastrointestinal disorders Stomatitis	3.3% 4/120 • Number of events 6 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	12.3% 15/122 • Number of events 20 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Gastrointestinal disorders Vomiting	9.2% 11/120 • Number of events 13 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	10.7% 13/122 • Number of events 28 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
General disorders Asthenia	16.7% 20/120 • Number of events 45 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	20.5% 25/122 • Number of events 38 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
General disorders Fatigue	5.8% 7/120 • Number of events 10 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	4.1% 5/122 • Number of events 5 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
General disorders Influenza like illness	5.0% 6/120 • Number of events 7 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	7.4% 9/122 • Number of events 13 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
General disorders Malaise	9.2% 11/120 • Number of events 14 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	7.4% 9/122 • Number of events 16 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
General disorders Oedema peripheral	15.0% 18/120 • Number of events 31 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	9.8% 12/122 • Number of events 17 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
General disorders Pain	18.3% 22/120 • Number of events 30 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	15.6% 19/122 • Number of events 39 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
General disorders Pyrexia	17.5% 21/120 • Number of events 28 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	23.8% 29/122 • Number of events 46 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Hepatobiliary disorders Hepatic function abnormal	5.0% 6/120 • Number of events 8 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	2.5% 3/122 • Number of events 3 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Infections and infestations Nasopharyngitis	5.8% 7/120 • Number of events 8 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	7.4% 9/122 • Number of events 14 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Infections and infestations Upper respiratory tract infection	13.3% 16/120 • Number of events 18 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	13.9% 17/122 • Number of events 20 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Investigations Alanine aminotransferase increased	46.7% 56/120 • Number of events 101 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	36.9% 45/122 • Number of events 83 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	8.3% 1/12 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Investigations Aspartate aminotransferase increased	40.8% 49/120 • Number of events 98 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	36.9% 45/122 • Number of events 95 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	16.7% 2/12 • Number of events 2 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Investigations Blood alkaline phosphatase increased	7.5% 9/120 • Number of events 13 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	7.4% 9/122 • Number of events 14 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	8.3% 1/12 • Number of events 2 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Investigations Blood bilirubin increased	11.7% 14/120 • Number of events 28 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	11.5% 14/122 • Number of events 20 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Investigations Blood creatinine increased	6.7% 8/120 • Number of events 10 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	9.0% 11/122 • Number of events 26 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	8.3% 1/12 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Investigations Blood triglycerides increased	3.3% 4/120 • Number of events 13 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	5.7% 7/122 • Number of events 16 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Investigations Gamma-glutamyltransferase increased	8.3% 10/120 • Number of events 12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	6.6% 8/122 • Number of events 11 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Investigations Weight decreased	5.0% 6/120 • Number of events 8 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	9.0% 11/122 • Number of events 12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Investigations Weight increased	13.3% 16/120 • Number of events 20 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	3.3% 4/122 • Number of events 5 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Metabolism and nutrition disorders Decreased appetite	11.7% 14/120 • Number of events 19 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	12.3% 15/122 • Number of events 15 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Metabolism and nutrition disorders Hyperglycaemia	6.7% 8/120 • Number of events 9 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	11.5% 14/122 • Number of events 25 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	8.3% 1/12 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Metabolism and nutrition disorders Hypoalbuminaemia	6.7% 8/120 • Number of events 10 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	9.0% 11/122 • Number of events 17 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	8.3% 1/12 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Metabolism and nutrition disorders Hypokalaemia	6.7% 8/120 • Number of events 24 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	14.8% 18/122 • Number of events 45 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	8.3% 1/12 • Number of events 1 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Metabolism and nutrition disorders Hypoproteinaemia	2.5% 3/120 • Number of events 3 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	5.7% 7/122 • Number of events 7 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Musculoskeletal and connective tissue disorders Arthralgia	2.5% 3/120 • Number of events 4 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	5.7% 7/122 • Number of events 10 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Musculoskeletal and connective tissue disorders Back pain	2.5% 3/120 • Number of events 5 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	5.7% 7/122 • Number of events 8 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Musculoskeletal and connective tissue disorders Pain in extremity	7.5% 9/120 • Number of events 13 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	3.3% 4/122 • Number of events 4 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Nervous system disorders Dizziness	9.2% 11/120 • Number of events 13 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	5.7% 7/122 • Number of events 8 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Nervous system disorders Headache	6.7% 8/120 • Number of events 11 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	7.4% 9/122 • Number of events 11 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Nervous system disorders Hypoaesthesia	6.7% 8/120 • Number of events 9 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	10.7% 13/122 • Number of events 13 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Nervous system disorders Neurotoxicity	5.8% 7/120 • Number of events 7 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	7.4% 9/122 • Number of events 10 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Psychiatric disorders Insomnia	8.3% 10/120 • Number of events 12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	8.2% 10/122 • Number of events 17 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Respiratory, thoracic and mediastinal disorders Cough	14.2% 17/120 • Number of events 21 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	21.3% 26/122 • Number of events 33 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	1.7% 2/120 • Number of events 2 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	5.7% 7/122 • Number of events 11 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Skin and subcutaneous tissue disorders Alopecia	33.3% 40/120 • Number of events 40 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	41.0% 50/122 • Number of events 53 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Skin and subcutaneous tissue disorders Dermatitis acneiform	1.7% 2/120 • Number of events 4 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	5.7% 7/122 • Number of events 8 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Skin and subcutaneous tissue disorders Nail discolouration	12.5% 15/120 • Number of events 15 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	9.8% 12/122 • Number of events 12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Skin and subcutaneous tissue disorders Pruritus	5.0% 6/120 • Number of events 7 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	6.6% 8/122 • Number of events 13 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Skin and subcutaneous tissue disorders Rash	9.2% 11/120 • Number of events 13 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	9.0% 11/122 • Number of events 22 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Vascular disorders Hypertension	6.7% 8/120 • Number of events 10 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	9.8% 12/122 • Number of events 15 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Cardiac disorders Palpitations	6.7% 8/120 • Number of events 16 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	2.5% 3/122 • Number of events 3 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Infections and infestations Urinary tract infection	5.0% 6/120 • Number of events 9 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	4.9% 6/122 • Number of events 8 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Metabolism and nutrition disorders Hyponatraemia	4.2% 5/120 • Number of events 5 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	6.6% 8/122 • Number of events 10 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.	0.00% 0/12 • From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: genentech@druginfo.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER