CLEOPATRA: A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00567190
• Collaborator: Hoffmann-La Roche (Industry)
• Enrollment: 808
• Locations: 322
• Arms: 2
• Actual Duration (Months): 129.3
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study was a Phase III, randomized, double-blind, placebo-controlled, multicenter international clinical trial conducted to investigate the use of pertuzumab in combination with trastuzumab and docetaxel as first-line treatment for participants with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Participants could have received one prior hormonal treatment for MBC. Participants may have received systemic breast cancer treatment in the neo-adjuvant or adjuvant setting, provided that the participant had experienced a disease-free interval (DFI) of greater than or equal to (≥)12 months from completion of adjuvant systemic treatment (excluding hormonal therapy) to metastatic diagnosis. Participants may have received trastuzumab and/or a taxane during the neo-adjuvant or adjuvant treatment.

Participants were randomized in 1:1 ratio to receive either pertuzumab or placebo, along with trastuzumab and docetaxel once every 3 weeks (q3w), during the treatment phase of the study until investigator-assessed radiographic or clinical progressive disease, unmanageable toxicity, or study termination. Participants in the Placebo arm were not allowed to receive open-label pertuzumab after discontinuation from study treatment. However, if any analysis of overall survival had met the predefined criteria for statistical significance, participants in the Placebo arm still on treatment were offered the option to receive open-label pertuzumab in addition to other study medications.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Pertuzumab; Drug: Placebo; Drug: Trastuzumab; Drug: Docetaxel	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 808 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer
• Actual Study Start Date: Feb 12, 2008
• Actual Primary Completion Date: May 13, 2011
• Actual Study Completion Date: Nov 23, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pertuzumab + Trastuzumab + Docetaxel Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Drug: Pertuzumab; Pertuzumab was administered as an intravenous (IV) loading dose of 840 milligrams (mg) q3w on Day 1 of Cycle 1 (1 Cycle length = 21 days), and 420 mg q3w on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, unmanageable toxicity, or study termination.; Other Names: Perjeta RO4368451 RG1273 ; Drug: Trastuzumab; Trastuzumab was administered as an IV loading dose of 8 milligrams per kilogram (mg/kg) q3w on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 6 mg/kg q3w on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, unmanageable toxicity, or study termination.; Other Names: Herceptin ; Drug: Docetaxel; Docetaxel was administered as an IV dose of 75 milligrams per square meter of body surface area (mg/m^2) q3w on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 75 mg/m^2 (up to 100 mg/m^2 as per treating physician discretion) q3w on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, unmanageable toxicity, or study termination. On or prior to Cycle 6, docetaxel was only to be discontinued for progressive disease or unmanageable toxicity. After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician.; Other Names: Taxotere
Placebo Comparator: Placebo + Trastuzumab + Docetaxel Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Drug: Placebo; Placebo (matching pertuzumab) was administered intravenously.; Drug: Trastuzumab; Trastuzumab was administered as an IV loading dose of 8 milligrams per kilogram (mg/kg) q3w on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 6 mg/kg q3w on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, unmanageable toxicity, or study termination.; Other Names: Herceptin ; Drug: Docetaxel; Docetaxel was administered as an IV dose of 75 milligrams per square meter of body surface area (mg/m^2) q3w on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 75 mg/m^2 (up to 100 mg/m^2 as per treating physician discretion) q3w on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, unmanageable toxicity, or study termination. On or prior to Cycle 6, docetaxel was only to be discontinued for progressive disease or unmanageable toxicity. After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician.; Other Names: Taxotere

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) Determined by an Independent Review Facility [Tumor assessments every 9 weeks from randomization to IRF-determined PD or death from any cause, whichever occurred first, up to the primary completion date (up to 3 years, 3 months)]

   PFS was defined as the time from randomization to first documented radiographical progressive disease (PD), as determined by an independent review facility (IRF) using RECIST version 1.0, or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first (Kaplan-Meier method). For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of ≥1 new lesion. For non-target lesions, PD was defined as the appearance of ≥1 new lesion or unequivocal progression of existing lesions. Participants without IRF-determined PD or who had not died within 18 weeks of their last IRF-determined, progression-free tumor assessment were censored at the date of the last IRF-reviewed, evaluable tumor assessment; those with no post-baseline tumor assessment and who had not died within 18 weeks of baseline were censored at 1 day.

Secondary Outcome Measures

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

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

2. Progression-Free Survival (PFS) Determined by the Investigator [Tumor assessments every 9 weeks from randomization to investigator-determined PD or death from any cause, whichever occurred first (median [range] time on study in pertuzumab vs. placebo arms: 201.8 [0.7-520.0] weeks vs. 138.0 [0.4-514.7] weeks)]

   PFS was defined as the time from randomization to first documented radiographical progressive disease (PD), as determined by the investigator using RECIST version 1.0, or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first (Kaplan-Meier method). For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of ≥1 new lesion. For non-target lesions, PD was defined as the appearance of ≥1 new lesion or unequivocal progression of existing lesions. Participants without PD or who had not died within 18 weeks of their last investigator-determined, progression-free tumor assessment were censored at the date of the last investigator tumor assessment; those with no post-baseline tumor assessment and who had not died within 18 weeks of baseline were censored at 1 day.

3. Objective Response Determined by an Independent Review Facility [Tumor assessments every 9 weeks from Baseline until IRF-determined progressive disease (PD), death, or first administration of next line of anti-cancer therapy (whichever occurred first), up to the primary completion date (up to 3 years, 3 months)]

   An objective response was defined as the percentage of participants with confirmed best overall response of complete response (CR) or partial response (PR) determined by an independent review facility (IRF) using RECIST v1.0 on two consecutive occasions ≥4 weeks apart. For target lesions, CR: disappearance of all target lesions; PR: ≥30% decrease in the sum of the longest diameter (LD) of target lesions (baseline sum LD as reference); PD: ≥20% increase in the sum of the LD of target lesions (smallest sum of the LD recorded as reference) or appearance of ≥1 new lesion; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase for PD. For non-target lesions, CR: disappearance of all non-target lesions; Incomplete/SD: persistence of ≥1 non-target lesions; PD: unequivocal progression of existing non-target lesions. 95% confidence intervals (CI) were calculated only for clinical responses using the Pearson-Clopper method.

4. Duration of Objective Response Determined by an Independent Review Facility [From initial IRF-confirmed objective response until IRF-determined progressive disease (PD), death, or first administration of next line of anti-cancer therapy (whichever occurred first), up to the primary completion date (up to 3 years, 3 months)]

   Duration of objective response (estimated using the Kaplan-Meier method) was defined as the time from the initial confirmed complete response (CR) or partial response (PR), the date of tumor assessment at which the CR/PR was first detected by the independent review facility (IRF) using RECIST version 1.0, until the date of IRF-determined progressive disease (PD), death from any cause within 18 weeks of the last tumor assessment, or first administration of next line of anti-cancer therapy (whichever occurred first). If the visit when the initial CR or PR was observed spanned multiple dates, the latest date was used. Only participants in the ITT analysis population with an IRF-determined objective response (CR or PR), observed prior to IRF-assessed PD, death or next line of anti-cancer therapy, were included in the analysis. Participants who did not progress or die after they had a confirmed response were censored at the date of their last IRF-evaluable tumor measurement.

5. Time to Symptom Progression [Every 9 weeks from Baseline until investigator-determined progressive disease, up to the primary completion date (up to 3 years, 3 months)]

   Time to symptom progression was defined as the time from randomization to the first symptom progression as measured by the Functional Assessment of Cancer Therapy-for patients with Breast Cancer (FACT-B) questionnaire with the Trial Outcomes Index-Physical/Functional/Breast (TOI-PFB) subscale. The FACT-B TOI-PFB subscale contains 24 items from 3 subsections of the FACT-B questionnaire: Physical well-being, functional well-being, and additional concerns for breast cancer patients (breast cancer subscale [BCS]). All items in the questionnaire were rated by the patient on a 5-point scale ranging from 0 ("not at all") to 4 ("very much"). The total score ranged from 0 to 96. A higher score indicates better perceived quality of life. A positive change score from baseline indicates improvement. Symptom progression was defined as a decrease from baseline of 5 points or more.

6. Overall Number of Participants Who Experienced at Least One Adverse Event, Including Serious and Non-Serious Adverse Events, by Most Severe Intensity (According to NCI-CTCAE v3.0) During the Treatment Period [Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)]

   Adverse event (AE) severity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 (NCI-CTCAE v3.0); 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. Only the most severe intensity was counted for multiple occurrences of the same AE in one participant. AEs reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for participants who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.

7. Overall Number of Adverse Events by Severity (NCI-CTCAE v3.0 All Grades and Grades 3 to 5) Per 100 Patient-Years of Exposure During the Treatment Period [From Baseline to 42 days after the last dose of study treatment (total patient-years of exposure on study treatment in Placebo vs. Pertuzumab arms: 526.81 vs. 989.88 patient-years)]

   Adverse event (AE) severity, including serious and non-serious AEs, was assessed according to the NCI-CTCAE version 3.0; if the AE was not specifically listed, the following grades of severity were used: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe; Grade 4 is life-threatening or disabling; and Grade 5 is death. Multiple occurrences of the same AE in 1 participant were counted multiple times. Only AEs that started during the overall study treatment period were included. The cutoff date for inclusion of events and for calculation of patient-years was the date of the most recent follow-up of the participant, defined as the last available date during the treatment period, excluding pre-treatment and safety follow-up data. Confidence intervals were calculated assuming the number of events followed a Poisson distribution. Data reported prior to the date of first crossover treatment were included under the Placebo arm for participants who crossed over from placebo to pertuzumab.

8. Cardiac-Related AEs to Monitor: Number of Participants Who Experienced at Least One Symptomatic Left Ventricular Dysfunction (LVD), Any LVD, or Serious AE Suggestive of Congestive Heart Failure by Severity During the Treatment Period [Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)]

   Cardiac-related adverse events (AEs) to monitor during the study included investigator-assessed symptomatic left ventricular dysfunction (LVD), any LVD, or a serious adverse event (SAE) suggestive of congestive heart failure (CHF). All cardiac-related AEs were graded for severity according to NCI-CTCAE v3.0. Asymptomatic (Grades 1-2) and symptomatic (Grades 3-5) left ventricular systolic dysfunction (LVSD) both coded to the MedDRA preferred term LVD. Investigator-assessed events of symptomatic LVD were also graded for severity of symptoms according to Classes I (least severe) to IV (most severe) of the New York Heart Association (NYHA) Classification. SAEs suggestive of CHF were identified as serious events from the Standardized MedDRA Query (SMQ) (Wide) 'Cardiac Failure'. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.

9. Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period [Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)]

   The clinical diagnoses listed in this table, excluding cardiac safety (summarized separately), were also selected as adverse events (AEs) to monitor based on clinical and nonclinical data for pertuzumab and the safety profile established for trastuzumab, monoclonal antibodies in general, and potential effects associated with HER receptor inhibition. Search strategies were defined by single or aggregate MedDRA Preferred Terms (PT) through Standardized MedDRA Queries (SMQ), where possible, or based on Roche AE Group Terms (AEGT). Diarrhoea AEs: High-Level Term (HLT) 'Diarrhoea (excl. infective)' and PT 'Diarrhoea infectious'. Leukopenic and Febrile Neutropenic Infections: AEs from 'Infections & Infestations' with start ≤14 days after start date of Grade ≥3 AEs in SMQ(narrow) 'Leukopenia' or PT 'Febrile neutropenia', respectively. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.

10. Overall Number of Participants Who Experienced at Least One Adverse Event Leading to Discontinuation of Any or All Study Medication [Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)]

    Participants could continue study treatment with pertuzumab/placebo plus trastuzumab when docetaxel was discontinued due to an adverse event (AE). Discontinuation of pertuzumab/placebo or trastuzumab due to an AE led to discontinuation of all study medication. The number of participants who discontinued any study medication due to an AE includes those who discontinued all study medication and those who discontinued docetaxel only and then continued on targeted therapy (note: some of these participants may have subsequently discontinued all treatment due to a separate AE). Multiple occurrences of the same adverse event in 1 participant was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for those who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.

11. Overall Number of Participants Who Experienced at Least One Adverse Event That Resulted in Interruption or Modification of Any Study Medication [Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)]

    Pertuzumab, trastuzumab, and docetaxel administration could have been delayed to assess or treat adverse events (AEs). Docetaxel dose reduction was allowed for myelosuppression, hepatic dysfunction, and other toxicities. No dose reduction was allowed for pertuzumab or trastuzumab. Multiple occurrences of the same adverse event in one participant was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for participants who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks

12. Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period [From Day 43 after discontinuation of all study medication to end of post-treatment follow-up period (up to 3 years)]

    The post-treatment period was defined as the period following the treatment discontinuation visit. Only the following new adverse events (AEs) should have been reported during the post-treatment follow-up period: 1. Cardiac events (regardless of causality or seriousness) that started up to 1 year after the last dose, except for symptomatic left ventricular systolic dysfunction (regardless of causality) that started up to 3 years after the last dose; and 2. Treatment-related serious AEs, regardless of start date. AEs are listed by Medical Dictionary for Regulatory Activities, Version 21.1 (MedDRA v21.1) System Organ Class (SOC) and Preferred Term (PT); PTs fall under the SOC that is listed immediately above it in the table. Multiple occurrences of the same AE in one participant was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for participants who crossed over from placebo to pertuzumab.

13. Number of Participants by Categories for the Maximum Absolute Decrease From Baseline in LVEF Value During the Treatment Period [Every 9 weeks from the date of randomization until Treatment Discontinuation Visit (see Description for time on study treatment per arm)]

    All participants were required to have an left ventricular ejection fraction (LVEF) ≥50% at baseline, as measured by echocardiogram (preferred) or multiple-gated acquisition (MUGA) scan. The same method of LVEF assessment and the same institution/facility used at baseline was used throughout the study, to the extent possible. The baseline value was defined as the last valid value recorded during the pre-treatment period before or on study Day 1. The maximum absolute decrease in LVEF value was defined as the lowest post-baseline value up to the end of the overall study treatment period. Data reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for participants who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.

14. Baseline LVEF Value and Change in LVEF From Baseline at Maximum Absolute Decrease Value During the Treatment Period [Every 9 weeks from the date of randomization until Treatment Discontinuation Visit (median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks)]

    All participants were required to have a left ventricular ejection fraction (LVEF) ≥50% at baseline, as measured by echocardiogram (preferred) or multiple-gated acquisition (MUGA) scan. The same method of LVEF assessment and the same institution/facility used at baseline was used throughout the study, to the extent possible. The baseline value was defined as the last valid value recorded during the pre-treatment period before or on study Day 1. The maximum absolute decrease in LVEF value was defined as the lowest post-baseline value up to the end of the overall study treatment period. Only data reported prior to the date of first crossover treatment were included for participants who crossed over from placebo to pertuzumab.

15. Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period [On Day 1 of every treatment cycle (1 cycle is 21 days) until Treatment Discontinuation Visit (see Description for time on study treatment per arm)]

    Clinical laboratory tests for blood biochemistry parameters were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest grade according to NCI-CTCAE v3.0. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks. ALP = alkaline phosphatase; GGT = gamma-glutamyl transferase; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase

16. Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period [On Day 1 (and Day 8 for some measures) of every treatment cycle (1 cycle is 21 days) until Treatment Discontinuation Visit (see Description for time on study treatment per arm)]

    Clinical laboratory tests for hematology parameters were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest grade according to NCI-CTCAE v3.0. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks. INR = International Normalized Ratio; PTT = partial thromboplastin time; WBC = white blood cell

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease, and candidate for chemotherapy. Participants with measurable and non-measurable disease are eligible (locally recurrent disease must not be amenable to resection with curative intent; participants with de novo Stage IV disease are eligible)

• Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC)

• Left ventricular ejection fraction (LVEF) ≥50 percent (%) at baseline (within 42 days of randomization)

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

• For women of childbearing potential and men with partners of childbearing potential, agreement to use a highly effective form of contraception and to continue its use for the duration of study treatment and for at least 7 months after the last dose of study treatment

Exclusion Criteria:

• History of anti-cancer therapy for MBC (with the exception of one prior hormonal regimen for MBC, which must be stopped prior to randomization)

• History of approved or investigative tyrosine kinase/HER inhibitors for breast cancer in any treatment setting, except trastuzumab used in the neoadjuvant or adjuvant setting

• History of systemic breast cancer treatment in the neo-adjuvant or adjuvant setting with a disease-free interval from completion of the systemic treatment (excluding hormonal therapy) to metastatic diagnosis of less than (<)12 months

• History of persistent Grade ≥2 hematologic toxicity resulting from previous adjuvant therapy

• Current peripheral neuropathy of National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 3.0, Grade ≥3 at randomization

• History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent

• Current clinical or radiographic evidence of central nervous system (CNS) metastases

• Computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain is mandatory in cases of clinical suspicion of brain metastases

• History of exposure to cumulative doses of anthracyclines

• Current uncontrolled hypertension or unstable angina

• History of congestive heart failure (CHF) of any New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (exception: atrial fibrillation or paroxysmal supraventricular tachycardia)

• History of myocardial infarction within 6 months of randomization

• History of LVEF decline to below 50% during or after prior trastuzumab neo-adjuvant or adjuvant therapy

• Current dyspnea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy

• Inadequate organ function, as defined in the protocol, within 28 days prior to randomization

• Current severe, uncontrolled systemic disease

• Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start or anticipation of the need for major surgery during the course of study treatment

• Pregnant or lactating women

• History of receiving any investigational treatment within 28 days of randomization

• Current known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)

• Receipt of IV antibiotics for infection within 14 days of randomization

• Current chronic daily treatment with corticosteroids (excluding inhaled steroids)

• Known hypersensitivity to any of the study drugs

• Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HonorHealth Research Institute - Bisgrove	Scottsdale	Arizona	United States	85258
2	NEA Baptist Clinic	Jonesboro	Arkansas	United States	72401
3	Central Hematology Oncology Medical Group Inc.	Alhambra	California	United States	91801
4	Pacific Cancer Medical Center	Anaheim	California	United States	92801
5	Comprehensive Blood/Cancer Ctr	Bakersfield	California	United States	93309
6	Kaiser Permanente - Baldwin Park	Baldwin Park	California	United States	91706
7	Tower Cancer Research Foundation	Beverly Hills	California	United States	90211
8	South Bay Oncology Hematology Partners	Campbell	California	United States	95008
9	Wilshire Oncology Medical Group	Corona	California	United States	92879
10	Compassionate Cancer Care	Fountain Valley	California	United States	92708
11	Pacific Coast Hematology/Oncology Medical Group	Fountain Valley	California	United States	92708
12	St. Jude Heritage Healthcare; Virgiia K.Crosson Can Ctr	Fullerton	California	United States	92835
13	Wilshire Onc Med Grp., Inc	Glendora	California	United States	91741
14	Wilshire Oncology Medical Group	La Verne	California	United States	91750
15	UCLA	Los Angeles	California	United States	90024
16	LAC USC Medical Center	Los Angeles	California	United States	90033
17	Cedars- Sinai Medical Center	Los Angeles	California	United States	90048
18	Ronald Reagan UCLA Medical Center Clin Lab	Los Angeles	California	United States	90095
19	TORI Central Administration	Los Angeles	California	United States	90095
20	UCLA Hematology / Oncology Clinic	Los Angeles	California	United States	90095
21	UCLA Med Ctr; Pharma Svcs	Los Angeles	California	United States	90095
22	Sutter Gould Medical Foundation; Clinical Research	Modesto	California	United States	95355
23	Kaiser Permanente - Oakland	Oakland	California	United States	94611
24	Ventura County Hematology-Oncology Specialists	Oxnard	California	United States	93030
25	UCLA Healthcare/Pasadena Oncology	Pasadena	California	United States	91105
26	Wilshire Oncology Medical Group	Pasadena	California	United States	91750
27	Bay Area Cancer Research Group, LLC	Pleasant Hill	California	United States	94523
28	Wilshire Oncology Medical Group	Pomona	California	United States	91767
29	Wilshire Oncology Medical Group	Rancho Cucamonga	California	United States	91730
30	UC Davis Cancer Center; Oncology	Sacramento	California	United States	95817
31	Kaiser Permanente San Diego; Hepatology Research	San Diego	California	United States	92154
32	K. Permanente - San Fransisco	San Francisco	California	United States	94115
33	K. Permanente - San Jose	San Jose	California	United States	95119
34	Sansum Santa Barbara Medical Foundation Clinic	Santa Barbara	California	United States	93105
35	Santa Barbara Hematology Oncology Medical Group, Inc.	Santa Barbara	California	United States	93105
36	UCLA Hematology/Oncology	Santa Monica	California	United States	90404
37	UCLA / Santa Clarita Valley Cancer Center	Valencia	California	United States	91355
38	Kaiser Permanente - Vallejo	Vallejo	California	United States	94589
39	K. Permanente - Walnut Creek	Walnut Creek	California	United States	94596
40	Wilshire Oncology Medical Group	West Covina	California	United States	91790
41	Innovative clinical research institute/American institute of research	Whittier	California	United States	90603
42	Georgetown University Medical Center Lombardi Cancer Center	Washington	District of Columbia	United States	20007
43	MedStar Washington Hosp Center	Washington	District of Columbia	United States	20010
44	Sibley Memorial Hospital	Washington	District of Columbia	United States	20016
45	Boca Raton Comprehensive Cancer Center	Boca Raton	Florida	United States	33428
46	Florida Cancer Specialists -Cape Coral (Cape Coral Pkwy)	Cape Coral	Florida	United States	33914
47	Florida Cancer Specialists - Cape Coral (Del Prado Blvd)	Cape Coral	Florida	United States	33990
48	Northwest Oncology/ Hematology Assoc.	Coral Springs	Florida	United States	33065-5701
49	UM Sylvester Deerfield Beach; Sylvester Cancer Ctr	Deerfield Beach	Florida	United States	33442
50	Florida Cancer Specialists - Englewood	Englewood	Florida	United States	34223
51	Florida Cancer Specialists - Fort Myers (New Hampshire Ct)	Fort Myers	Florida	United States	33901-8101
52	Florida Cancer Specialists - Broadway	Fort Myers	Florida	United States	33901
53	Florida Cancer Specialists; SCRI	Fort Myers	Florida	United States	33901
54	Florida Cancer Specialists-Broadway, Fort Myers	Fort Myers	Florida	United States	33908
55	Private Practice Robert R. Carroll, Md, Pa	Gainesville	Florida	United States	32605
56	Memorial Cancer Institute	Hollywood	Florida	United States	33021
57	Memorial Regional Hospital	Hollywood	Florida	United States	33021
58	Lakeland Regional Cancer Center	Lakeland	Florida	United States	33804-1057
59	Jackson Memorial Hospital	Miami	Florida	United States	33136
60	University of Miami School of Medicine	Miami	Florida	United States	33136
61	Florida Cancer Specialists - Goodlette, Naples	Naples	Florida	United States	34102
62	Florida Cancer Specialists - Pine Ridge, Naples	Naples	Florida	United States	34119
63	Private Practice	Orlando	Florida	United States	32804
64	Breast Cancer Centre at Memorial Hospital West	Pembroke Pines	Florida	United States	33028
65	Florida Cancer Specialists - Port Charlotte	Port Charlotte	Florida	United States	33980
66	Florida Cancer Specialists; Sarasota	Sarasota	Florida	United States	34232
67	Bay Area Oncology	Tampa	Florida	United States	33607
68	Florida Cancer Specialists - Venice (S. Tamiami Tr)	Venice	Florida	United States	33980
69	Florida Cancer Specialists - Sunset Lake, Venice	Venice	Florida	United States	34292
70	Cleveland Clinic Florida	Weston	Florida	United States	33331
71	Northeast Georgia Medical Center; Oncology Research Dept-5C	Gainesville	Georgia	United States	30501
72	Central Georgia Hematology Oncology Associates	Macon	Georgia	United States	31201
73	Northwest Georgia Oncology Centers, a Service of WellStar Cobb Hospital	Marietta	Georgia	United States	30060
74	Central GA Cancer Care	Warner Robins	Georgia	United States	31088-2259
75	Elmhurst Hospital	Elmhurst	Illinois	United States	60126
76	Hematology Oncology Consultants Ltd	Naperville	Illinois	United States	60540
77	Quincy Medical Group	Quincy	Illinois	United States	62301
78	Midwestern Regional Medical Center; Office of Research	Zion	Illinois	United States	60099
79	Monroe Medical Associates - Hobart	Hobart	Indiana	United States	46342
80	St. Mary Medical Center	Hobart	Indiana	United States	46432
81	Hematology-Oncology of Indiana, Pc	Indianapolis	Indiana	United States	46260
82	Community Hospital; Pharmacy	Munster	Indiana	United States	46321
83	Northwest Oncology	Munster	Indiana	United States	46321
84	Monroe Medical Associates	Munster	Indiana	United States	46375
85	Family Medicine Vincennes	Vincennes	Indiana	United States	47591
86	Uni of Iowa Hospital&Clinic; Holden Comprehens. Cancer Ctr	Iowa City	Iowa	United States	52242
87	University of Kansas; Medical Center & Medical pavilion	Westwood	Kansas	United States	66205
88	Cancer Center of Kansas	Wichita	Kansas	United States	67214-3728
89	Jewish Cancer Care	Louisville	Kentucky	United States	40245
90	Cancer Center of Acadiana at Lafayette General	Lafayette	Louisiana	United States	70506
91	Christus Schumpert Health System	Shreveport	Louisiana	United States	71101-1978
92	Private Practice- Carolyn Hendricks, MD	Bethesda	Maryland	United States	20817
93	Boston Medical Center	Boston	Massachusetts	United States	02118-2393
94	Berkshire Hematology, Oncology Pc	Pittsfield	Massachusetts	United States	01201
95	Cancer & Hematology Centers of Western Michigan	Grand Rapids	Michigan	United States	49503
96	Cancer & Hematology Center of West Michigan	Grand Rapids	Michigan	United States	49546
97	Oncology Care Associates PLLC	Saint Joseph	Michigan	United States	49085
98	Southdale Cancer Clinic U of M Medical Center, Fairview- Edina	Edina	Minnesota	United States	55435
99	US Oncology Research at Minnesota Oncology	Minneapolis	Minnesota	United States	55404
100	Minneapolis Oncology Hamatology PA	Minneapolis	Minnesota	United States	55407-3799
101	The Jones Clinic, PC	New Albany	Mississippi	United States	38652
102	St. Vincent Frontier Cancer Center	Billings	Montana	United States	59101
103	Southeast Nebraska Cancer Center;; Southeast Nebraska Hematology and Oncology	Lincoln	Nebraska	United States	68510
104	Norfolk Oncology Consultants	Norfolk	Nebraska	United States	68701
105	Hematology-Oncology Consultants, Pc	Omaha	Nebraska	United States	68122
106	Southern Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
107	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
108	St. Barnabas Cancer Center	Livingston	New Jersey	United States	07039
109	Oncology and Hematology Specialists	Mountain Lakes	New Jersey	United States	07046
110	San Juan Oncology Associates	Farmington	New Mexico	United States	87401
111	Brockport-Interlakes Foundation	Brockport	New York	United States	14420
112	Canandaigua-Interlakes Found	Canandaigua	New York	United States	14420
113	Geneva-Interlakes Foundation	Geneva	New York	United States	14456
114	ProHEALTH Care Associates LLP	Lake Success	New York	United States	11042
115	Beth Israel Comprehensive Cancer Center Pharmacy	New York	New York	United States	10011
116	The Women'sOncology & Wellness Practice	New York	New York	United States	10016
117	Upstate Ny Cancer Research & Education Foundation	Rochester	New York	United States	14623
118	Duke University Medical Center	Durham	North Carolina	United States	27710
119	Carolina Oncology Specialists, PA - Hickory	Hickory	North Carolina	United States	28602
120	Carolina BioOncology Institute, PLCC	Huntersville	North Carolina	United States	28078
121	NW Carolina Onc & Hem	Lenoir	North Carolina	United States	28645
122	Gabrail Cancer Center	Canton	Ohio	United States	44718
123	Oncology Hematology Care Inc	Cincinnati	Ohio	United States	45242
124	Hema Onc Conslts-Grant Ave	Columbus	Ohio	United States	43215
125	The Mark H. Zangmeister Ctr; Mid Ohio Onc/Hem Inc.	Columbus	Ohio	United States	43219
126	Hematology Onc Consultants	Columbus	Ohio	United States	43228
127	Gabrail Cancer Center	Dover	Ohio	United States	44622
128	Hematology Oncology Consultants (NWK)	Granville	Ohio	United States	43023
129	Medical College of Ohio; Cancer Institute	Toledo	Ohio	United States	43614
130	Mercy Physicians of Oklahoma	Oklahoma City	Oklahoma	United States	73120
131	CA Care Associates-OK Oncology and Hematology	Tulsa	Oklahoma	United States	74104
132	Cancer Care Assoc-S. Ingo	Tulsa	Oklahoma	United States	74133
133	OK Oncology & Hematology PC	Tulsa	Oklahoma	United States	74136
134	Cons in Med Onc and Hem	Darby	Pennsylvania	United States	19026
135	Consultants in Medical Oncology/Hematology	Drexel Hill	Pennsylvania	United States	19026
136	Armstrong County Memorial Hospital	Kittanning	Pennsylvania	United States	16201
137	Conslts in Med Onc (Newtown); Bryn Mawr Health Canc Ctr	Newtown Square	Pennsylvania	United States	19073
138	Uni of Pittsburgh; Magee-Women'S Hospital	Pittsburgh	Pennsylvania	United States	15213
139	Consultants Med Onc & Hem	Ridley Park	Pennsylvania	United States	19078
140	Erlanger Health System; Oncology Research	Chattanooga	Tennessee	United States	37403
141	SCRI Tennessee Oncology Chattanooga	Chattanooga	Tennessee	United States	37404
142	McLeod Cancer and Blood Center	Johnson City	Tennessee	United States	37604
143	University of Tennessee Cancer Institute;Hem-Onc Consultants	Knoxville	Tennessee	United States	37920
144	Sarah Cannon Cancer Center - Tennessee Oncology, Pllc	Nashville	Tennessee	United States	37203
145	Park Plaza	Houston	Texas	United States	77004
146	Southwest	Houston	Texas	United States	77008
147	St. Joseph's	Houston	Texas	United States	77008
148	Memorial City-Main Office	Houston	Texas	United States	77024
149	Oncology Consultants	Houston	Texas	United States	77024
150	St. Luke's	Houston	Texas	United States	77030
151	Willowbrook	Houston	Texas	United States	77070
152	Katy-Christus St. Catherine	Katy	Texas	United States	77450
153	South Texas Oncology Hematology	San Antonio	Texas	United States	78258
154	Oncology Consultants - Sugar Land	Sugar Land	Texas	United States	77479
155	Northern Utah Associates	Ogden	Utah	United States	84403
156	Community Cancer Center Rutland Regional Medical Center	Rutland	Vermont	United States	05701
157	Wellmonth Physician Services	Bristol	Virginia	United States	24201
158	Northwest Medical Specialties	Tacoma	Washington	United States	98405
159	St. Mary Medical Center	Walla Walla	Washington	United States	99362
160	Sanatorio Güemes; Oncología	Buenos Aires		Argentina	1180
161	Centro de Oncologia e Investigacion Buenos Aires (COIBA)	Buenos Aires		Argentina	B1884BBF
162	Instituto Medico Especializado (IME); Oncologia	Caba		Argentina	1405
163	Center Instituto Médico Privado I.M.P.; Oncology	Chaco-resistencia		Argentina	3400
164	Policlinica Privada Site la Plata SA; Oncology	La Plata		Argentina	B1902CMK
165	Unidad Oncológica De Neuquén	Neuquén		Argentina	Q8300HDH
166	Hosp Provincial D. Centenarios; Oncology Dept	Rosario		Argentina	S2002KDS
167	Clinica Amo - Assistencia Medica Em Oncologia	Salvador	BA	Brazil	41950-610
168	Crio - Centro Regional Integrado de Oncologia	Fortaleza	CE	Brazil	60336-550
169	Centro Goiano de Oncologia - CGO	Goiania	GO	Brazil	74140-050
170	Instituto Nacional de Cancer - INCa; Oncologia	Rio de Janeiro	RJ	Brazil	20560-120
171	Hospital Universitario Clementino Fraga Filho - UFRJ; Oncologia	Rio de Janeiro	RJ	Brazil	21941-590
172	Hospital de Caridade de Ijui; Oncologia	Ijui	RS	Brazil	98700-000
173	Santa Casa de Misericordia de Porto Alegre	Porto Alegre	RS	Brazil	90020-090
174	Hospital das Clinicas - UFRGS	Porto Alegre	RS	Brazil	90035-903
175	Hospital Nossa Senhora da Conceicao	Porto Alegre	RS	Brazil	91350-200
176	Hospital Amaral Carvalho	Jau	SP	Brazil	17210-120
177	Hospital das Clinicas - FMUSP Ribeirao Preto	Ribeirao Preto	SP	Brazil	14048-900
178	Faculdade de Medicina do ABC - FMABC; Oncologia e Hematologia	Santo Andre	SP	Brazil	09060-650
179	Iso - Inst. Santista de Oncologia	Santos	SP	Brazil	11075-350
180	Instituto do Cancer Arnaldo Vieira de Carvalho - ICAVC; Pesquisa Clinica	Sao Paulo	SP	Brazil	01221-020
181	Instituto do Cancer do Estado de Sao Paulo - ICESP	Sao Paulo	SP	Brazil	01246-000
182	Hospital Perola Byington	Sao Paulo	SP	Brazil	01317-000
183	Inst. Brasileiro de Controle Ao Cancer; Oncologia Clinica / Quimioterapia	Sao Paulo	SP	Brazil	03102-002
184	Hospital Estadual do Servidor Publico	Sao Paulo	SP	Brazil	04039-901
185	Instituto de Oncologia de Sorocaba - CEPOS	Sorocaba	SP	Brazil	18030-005
186	St. Michael'S Hospital	Toronto	Ontario	Canada	M5B 1W8
187	Jilin Cancer Hospital	Changchun		China	130012
188	Fuzhou General Hospital, PLA Nanjing Military Area Command	Fuzhou		China	110016
189	Zhejiang Cancer Hospital	Hangzhou		China	310022
190	Fudan University Shanghai Cancer Center	Shanghai City		China	200120
191	Shanghai First People's Hospital	Shanghai		China	200080
192	Hospital Cima San Jose; Oncology	San Jose		Costa Rica	10103
193	Clinical Hospital Sisters of Mercy	Zagreb		Croatia	10000
194	University Hospital Centre Zagreb; Clinic For Oncology	Zagreb		Croatia	10000
195	Solca Guayaquil- Sociedad de Lucha Contra El Cáncer; Oncology	Guayaquil		Ecuador	EC090112
196	Teodoro Maldonado Carbo Hospital; Oncology Service	Guayaquil		Ecuador	EC090150
197	Hospital Carlos Andrade Marin; Servicio de Oncología	Quito		Ecuador	2569
198	Hospital Solca Quito; Oncologia	Quito		Ecuador	EC170124
199	Tampere University Hospital; Dept of Oncology	Tampere		Finland	33520
200	Turku Uni Central Hospital; Oncology Clinics	Turku		Finland	20520
201	Centre Oncologie Du Pays Basque	Bayonne		France	64100
202	Clinique Tivoli; Sce Radiotherapie	Bordeaux		France	33000
203	Centre Georges Francois Leclerc; Oncologie 3	Dijon		France	21079
204	Centre Hospitalier Departemental Les Oudairies	La Roche Sur Yon		France	85925
205	Centre Jean Bernard	Le Mans		France	72015
206	Centre Antoine Lacassagne; Hopital De Jour A2	Nice		France	06189
207	Ico Rene Gauducheau; Oncologie	Saint Herblain		France	44805
208	Groupe Hospitalier Sud; Oncologie Radiotherapie	Salouel		France	80480
209	Onkologischer Schwerpunkt am Oskar-Helene-Heim; Dres. Herrenberger, Keitel-Wittig u. Kirsch	Berlin		Germany	14195
210	Onkologische Schwerpunktpraxis Bielefeld; Haemotologie & Internistische onkologie	Bielefeld		Germany	33604
211	Universitätsklinikum Essen; Zentrum Für Frauenheilkunde	Essen		Germany	45122
212	Universitätsklinikum Halle (Saale); Universitätsklinik Und Poliklinik Für Gynäkologie	Halle		Germany	06120
213	Universitätsklinikum Hamburg-Eppendorf; Frauenklinik	Hamburg		Germany	20246
214	Nationales Centrum für Tumorerkrankungen (NCT) ; Gyn. Onk. Frauenklinik; Uniklinikum Heidelberg	Heidelberg		Germany	69120
215	St. Elisabeth Krankenhaus Köln GmbH; Gynäkologie und Geburtshilfe	Koeln		Germany	50935
216	Universitätsmedizin Mainz; Klinik u. Poliklinik f. Geburtshilfe u. Frauenheilkunde	Mainz		Germany	55131
217	Krankenhaus Rheinfelden; Frauenklinik	Rheinfelden		Germany	79618
218	Robert-Bosch-Krankenhaus; Hämatologie, Onkologie und Palliativmedizin	Stuttgart		Germany	70376
219	Klinikum Mutterhaus der Borromaeerinnen gGmbH; Haematologie/Onkologie	Trier		Germany	54290
220	Universitätsklinik Tübingen; Frauenklinik	Tübingen		Germany	72076
221	Haematologisch-Onkologische Praxis; Dr. med. Christoph Maintz und Matthias Groschek	Wuerselen		Germany	52146
222	Grupo Angeles	Guatemala City		Guatemala	01015
223	Therapeutic Research Inst. & Lab S.A. (Trial)	Guatemala City		Guatemala	01015
224	Centro Oncologico S.A.	Guatemala		Guatemala	01010
225	Pamela Youde Nethersole Eastern Hospital; Clinical Oncology	Hong Kong		Hong Kong
226	Prince of Wales Hosp; Dept. Of Clinical Onc	Shatin		Hong Kong
227	Policlinico Ospedaliero Ss Annunziata; U.O. Di Clinica Oncologica	Chieti	Abruzzo	Italy	66100
228	IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica	Meldola	Emilia-Romagna	Italy	47014
229	Ospedale Provinciale Santa Maria delle Croci	Ravenna	Emilia-Romagna	Italy	48100
230	Ausl Frosinone - Ospedale Umberto I; Divisione Di Oncologia	Frosinone	Lazio	Italy	03100
231	Az. Osp. Spedali Civili; Divisione Di Oncologia - Iii Medicina	Brescia	Lombardia	Italy	25123
232	Ospedale Di Macerata; Oncologia	Macerata	Marche	Italy	62100
233	Fondazione Del Piemonte Per L'oncologia IRCC Di Candiolo	Candiolo	Piemonte	Italy	10060
234	Ospedale Antonio Perrino; Oncologia Medica	Brindisi	Puglia	Italy	72100
235	Azienda Sanitaria S. Maria Annunziata; S. C. Oncologia Medica	Antella (FI)	Toscana	Italy	50011
236	Ospedale Misericordia E Dolce; Oncologia Medica	Prato	Toscana	Italy	59100
237	Aichi Cancer Center Hospital, Breast Oncology	Aichi		Japan	464-8681
238	Chiba Cancer Center; Breast Surgical Oncology	Chiba		Japan	260-8717
239	National Cancer Center Hospital East; Breast and Medical Oncology	Chiba		Japan	277-8577
240	Natl Hosp Org Shikoku; Cancer Ctr, Surgery	Ehime		Japan	791-0280
241	Kitakyushu Municipal Medical Center, Surgery	Fukuoka		Japan	802-0077
242	National Hospital Organization Kyushu Cancer Center;Breast Oncology	Fukuoka		Japan	811-1395
243	Gunma University Hospital; Department of Thoracic and Visceral Organ Surgery	Gunma		Japan	371-8511
244	Iwate Med Univ School of Med; Surgery	Iwate		Japan	020-8505
245	Sagara Hospital; Breast Surgery	Kagoshima		Japan	892-0833
246	St. Marianna University School of Medicine Hospital, Breast and Endocrine Surgery	Kanagawa		Japan	216-8511
247	Tokai University Hospital, Breast and Endocrine Surgery	Kanagawa		Japan	259-1193
248	Kumamoto City Hospital, Breast and Endocrine Surgery	Kumamoto		Japan	862-8505
249	Kumamoto Shinto General Hospital; Breast Cancer Center	Kumamoto		Japan	862-8655
250	Kyoto University Hospital; Breast Surgery	Kyoto		Japan	606-8507
251	Niigata Cancer Ctr Hospital; Breast Surgery	Niigata		Japan	951-8566
252	OSAKA CITY GENERAL HOSPITAL;Medical Oncology	Osaka		Japan	534-0021
253	National Hospital Organization Osaka National Hospital; Breast Surgery	Osaka		Japan	540-0006
254	Osaka University Hospital; Breast and Endocrine Surgery	Osaka		Japan	565-0871
255	Saitama Medical University International Medical Center; Medical Oncology	Saitama		Japan	350-1298
256	Saitama Cancer Center, Breast Oncology	Saitama		Japan	362-0806
257	Shizuoka Cancer Center; Female Internal Medicine	Shizuoka		Japan	411-8777
258	Shizuoka General Hospital; Breast Surgery	Shizuoka		Japan	420-8527
259	Jichi Medical University; Dept of Clinical Oncology	Tochigi		Japan	329-0498
260	National Cancer Center Hospital; Breast and Medical Oncology	Tokyo		Japan	104-0045
261	St. Luke's Internat. Hospital, Breast Surgical Oncology	Tokyo		Japan	104-8560
262	Tokyo Metropolitan; Komagome Hospital, Surgery	Tokyo		Japan	113-8677
263	The Cancer Inst. Hosp. of JFCR; Breast Oncology Center	Tokyo		Japan	135-8550
264	Tokyo Medical Uni. Hospital; Breast Oncology	Tokyo		Japan	160-0023
265	National Cancer Center; Medical Oncology	Gyeonggi-do		Korea, Republic of	410-769
266	Seoul National Uni Hospital; Dept. of Internal Medicine/Hematology/Oncology	Seoul		Korea, Republic of	03080
267	Yonsei Uni College of Medicine, Severance Hospital; Internal Medicine Dept.	Seoul		Korea, Republic of	120-752
268	Samsung Medical Centre; Division of Hematology/Oncology	Seoul		Korea, Republic of	135-710
269	Asan Medical Center, Uni Ulsan Collegemedicine; Dept.Internal Medicine / Divisionhematology/Oncology	Seoul		Korea, Republic of	138-736
270	Daugavpils Regional Hospital	Daugavpils		Latvia	5417
271	Rigas Austrumu Kliniska Universitates slimnica, Latvijas Onkologijas centrs	Riga		Latvia	LV 1079
272	P.Stradins Clinical University Hospital, Oncology Centre	Riga		Latvia	LV-1002
273	Hospital Angeles Metropolitano; Room 220	Mexico City	Mexico CITY (federal District)	Mexico	06760
274	Centro Oncologico Estatal ISSEMYM	Toluca		Mexico	50180
275	Clinical Hospital; Oncology Department	Bitola		North Macedonia	7000
276	Institute of Radiotherapy Oncology	Skopje		North Macedonia	1000
277	Private Health Organization Acibadem Sistina Hospital	Skopje		North Macedonia	1000
278	Cebu Cancer Institute; Perpetual Succour Hospital	Cebu City		Philippines	6000
279	Veterans Memorial Medical Center; Oncology	Quezon City		Philippines	1101
280	St Luke'S Medical Centre; Oncology	Quezon City		Philippines	1114
281	Samodzielny Publiczny Kliniczny Nr 1 W Lublinie; Klinika Chirurgii Onkologicznej	Lublin		Poland	20-081
282	COZL Oddzial Onkologii Klinicznej z pododdzialem Chemioterapii Dziennej	Lublin		Poland	20-090
283	Oddzial Chemioterapii Szpitala Klinicznego Nr 1 w Poznaniu	Poznan		Poland	60-569
284	Zachodniopomorskie Centrum Onkologii, Osrodek Innowacyjnosci, Rozwoju i Badan Klinicznych	Szczecin		Poland	71-730
285	Centrum Onkologii - Instytut im. Marii Skłodowskiej-Curie Klinika Nowotworów Piersi i Chirurgii	Warszawa		Poland	02-781
286	FSBI"National Medical Research Center of Oncology named after N.N.Petrov" MHRF	St Petersburg	Leningrad	Russian Federation	197758
287	Ivanovo Regional Oncology Dispensary	Ivanovo		Russian Federation	153040
288	Regional Oncology Hospital Of Kursk; Chemotherapy	Kislino, Kursk Region		Russian Federation	305524
289	Blokhin Cancer Research Center; Combined Treatment	Moscow		Russian Federation	115478
290	Russian Oncology Research Center n.a. N.N. Blokhin Dpt of Clinical Pharmacology and Chemotherapy	Moscow		Russian Federation	115478
291	Omsk Region Clinical Oncology Dispensary; 1St Sergical Department	Omsk		Russian Federation	644013
292	State Inst. Of Healthcare Orenburg Regional Clinical Oncology Dis	Orenburg		Russian Federation	460021
293	SBI of Healthcare Samara Regional Clinical Oncology Dispensary	Samara		Russian Federation	443031
294	SBI of Healthcare Leningrad Regional Oncology Dispensary	St Petersburg		Russian Federation	191104
295	National University Hospital; National University Cancer Institute, Singapore (NCIS)	Singapore		Singapore	119228
296	National Cancer Centre; Medical Oncology	Singapore		Singapore	169610
297	Hospital Universitario de Canarias;servicio de Oncologia	La Laguna	Tenerife	Spain	38320
298	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona		Spain	08035
299	Hospital Duran i Reynals; Oncologia	Barcelona		Spain	08907
300	Complejo Hospitalario de Jaen-Hospital Universitario Medico Quirurgico; Servicio de Oncologia	Jaen		Spain	23007
301	Complejo Hospitalario Universitario A Coruña (CHUAC, Materno Infantil), Oncología	La Coruña		Spain	15006
302	Hospital Universitari Arnau de Vilanova de Lleida; Servicio de Oncologia	Lerida		Spain	25198
303	Centro Oncologico MD Anderson Internacional; Servicio de Oncologia	Madrid		Spain	28033
304	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid		Spain	28041
305	Hospital Clinico Universitario Virgen de la Victoria; Servicio de Oncologia	Malaga		Spain	29010
306	Chulalongkorn Hospital; Medical Oncology	Bangkok		Thailand	10330
307	National Cancer Inst.	Bangkok		Thailand	10400
308	Rajavithi Hospital; Division of Medical Oncology	Bangkok		Thailand	10400
309	Ramathibodi Hospital; Dept of Med.-Div. of Med. Onc	Bangkok		Thailand	10400
310	Faculty of Med. Siriraj Hosp.; Med.-Div. of Med. Oncology	Bangkok		Thailand	10700
311	Songklanagarind Hospital; Department of Oncology	Songkhla		Thailand	90110
312	Broomfield Hospital; Oncology	Chelmsford		United Kingdom	CM1 7ET
313	St James Uni Hospital; Icrf Cancer Medicine Research Unit	Leeds		United Kingdom	LS9 7TF
314	Leicester Royal Infirmary; Dept. of Medical Oncology	Leicester		United Kingdom	LE1 5WW
315	St. Bartholomew'S Hospital; Dept of Medical Oncology	London		United Kingdom	EC1A 7BE
316	Royal Free Hospital; Dept of Oncology	London		United Kingdom	NW3 2QG
317	St George'S Hospital; Oncology Research Office /Oncology Opd	London		United Kingdom	SW17 ORE
318	Charing Cross Hospital; Medical Oncology.	London		United Kingdom	W6 8RF
319	Mount Vernon Hospital; Centre For Cancer Treatment	Northwood		United Kingdom	HA6 2RN
320	Royal Cornwall Hospital; Dept of Clinical Oncology	Truro		United Kingdom	TR1 3LJ
321	Southend Hospital; Oncology Dept	Westcliffe-on-sea		United Kingdom	SS0 0RY
322	The Clatterbridge Cancer Ctr For Oncolgy	Wirral		United Kingdom	CH63 4JY

Sponsors and Collaborators

• Genentech, Inc.
• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Genentech, Inc./Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT00567190
• Other Study ID Numbers: TOC4129g; WO20698; 2007-002997-72
• First Posted: Dec 4, 2007
• Last Update Posted: Dec 13, 2019
• Last Verified: Dec 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Genentech, Inc.: Herceptin; Breast cancer; MBC; Taxotere; HER2; HER2 positive breast cancer; HER2 + breast cancer; HER2-positive; HER2-positive metastatic breast cancer
• Additional relevant MeSH terms: Breast Neoplasms; Docetaxel; Trastuzumab; Pertuzumab

Study Results

Participant Flow

Pre-assignment Detail	A total of 1196 patients were screened for the study, of whom a total of 808 participants were randomized to one of the two treatment arms.

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Period Title: Overall Study
STARTED	402	406
Did Not Receive Any Study Treatment	2	2
Received at Least One Dose of Pertuzumab	399	9
Received at Least One Dose of Placebo	1	395
Crossover From Placebo to Pertuzumab	0	50
COMPLETED	119	73
NOT COMPLETED	283	333

Baseline Characteristics

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel	Total
Arm/Group Description	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Total of all reporting groups
Overall Participants	402	406	808
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.4 (10.94)	53.5 (11.35)	53.5 (11.14)
Sex: Female, Male (Count of Participants)
Female	402 100%	404 99.5%	806 99.8%
Male	0 0%	2 0.5%	2 0.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	39 9.7%	44 10.8%	83 10.3%
Not Hispanic or Latino	362 90%	362 89.2%	724 89.6%
Unknown or Not Reported	1 0.2%	0 0%	1 0.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 0.7%	4 1%	7 0.9%
Asian	128 31.8%	133 32.8%	261 32.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	10 2.5%	20 4.9%	30 3.7%
White	245 60.9%	235 57.9%	480 59.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	16 4%	14 3.4%	30 3.7%
Region (Count of Participants)
Asia	125 31.1%	128 31.5%	253 31.3%
Europe	154 38.3%	152 37.4%	306 37.9%
North America	67 16.7%	68 16.7%	135 16.7%
South America	56 13.9%	58 14.3%	114 14.1%
Prior Treatment Status (Count of Participants)
Adjuvant or Neo-Adjuvant Therapy	184 45.8%	192 47.3%	376 46.5%
De Novo	218 54.2%	214 52.7%	432 53.5%
Independent-Review Facility (IRF)-Determined Disease Status at Screening (Count of Participants)
Measurable Disease	343 85.3%	336 82.8%	679 84%
Non-Measurable Disease	44 10.9%	43 10.6%	87 10.8%
Not Evaluated	15 3.7%	27 6.7%	42 5.2%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) Determined by an Independent Review Facility
Description	PFS was defined as the time from randomization to first documented radiographical progressive disease (PD), as determined by an independent review facility (IRF) using RECIST version 1.0, or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first (Kaplan-Meier method). For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of ≥1 new lesion. For non-target lesions, PD was defined as the appearance of ≥1 new lesion or unequivocal progression of existing lesions. Participants without IRF-determined PD or who had not died within 18 weeks of their last IRF-determined, progression-free tumor assessment were censored at the date of the last IRF-reviewed, evaluable tumor assessment; those with no post-baseline tumor assessment and who had not died within 18 weeks of baseline were censored at 1 day.
Time Frame	Tumor assessments every 9 weeks from randomization to IRF-determined PD or death from any cause, whichever occurred first, up to the primary completion date (up to 3 years, 3 months)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: All randomized participants

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	402	406
Median (95% Confidence Interval) [Months]	18.5	12.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	The null hypothesis (H0) was that the survival distributions of PFS in the two treatments arms (pertuzumab vs. placebo) are the same. The alternative hypothesis (H1) was that the survival distribution of PFS in the experimental arm (pertuzumab) and control arm (placebo) are different.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Tested at two-sided 5% significance level
	Method	Log Rank (stratified)
	Comments	Stratified by prior treatment status and region
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.51 to 0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is comparing Pertuzumab arm with Placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	The null hypothesis (H0) was that the survival distributions of PFS in the two treatments arms (pertuzumab vs. placebo) are the same. The alternative hypothesis (H1) was that the survival distribution of PFS in the experimental arm (pertuzumab) and control arm (placebo) are different.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Tested at two-sided 5% significance level
	Method	Log Rank (unstratified)
	Comments	Unstratified
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.52 to 0.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is comparing Pertuzumab arm with Placebo arm.

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population: All randomized participants

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	402	406
End-of-Study OS Analysis	57.1	40.8
Event-Driven Final OS Analysis	56.5	40.8
Second Interim OS Analysis	NA	37.6
First Interim OS Analysis	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	End-of-Study OS Analysis: This end-of-study OS analysis is considered exploratory only as the confirmatory OS analysis for statistical interpretation had previously occurred at the second interim OS analysis.
	Type of Statistical Test	Superiority
	Comments	Exploratory
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Exploratory
	Method	Log Rank (stratified)
	Comments	Stratified by prior treatment status and region.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.58 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is comparing Pertuzumab arm with Placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	Event-Driven Final OS Analysis: This final OS analysis was event-driven and planned to take place after a total of 385 deaths had occurred. It is considered exploratory only as the confirmatory OS analysis for statistical interpretation had previously occurred at the second interim OS analysis.
	Type of Statistical Test	Superiority
	Comments	Exploratory
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Exploratory
	Method	Log Rank (stratified)
	Comments	Stratified by prior treatment status and region.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.56 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is comparing Pertuzumab arm with Placebo arm.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	Second Interim OS Analysis: For this second interim OS analysis, the pre-defined O'Brien-Fleming stopping boundary for the Lan-DeMets α-spending function was: HR≤0.739, p≤0.0138.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments	The threshold for statistical significance was HR≤0.739, p≤0.0138.
	Method	Log Rank (stratified)
	Comments	Stratified by prior treatment status and region.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.52 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (HR) is comparing Pertuzumab arm with Placebo arm.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	First Interim OS Analysis: For this first interim OS analysis, the pre-defined O'Brien-Fleming stopping boundary for the Lan-DeMets α-spending function was: HR≤0.603, p≤0.0012.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0050
	Comments	The threshold for statistical significance was HR≤0.603, p≤0.0012.
	Method	Log Rank (stratified)
	Comments	Stratified by prior treatment status and region.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.47 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (HR) is comparing pertuzumab with placebo arms.

3. Secondary Outcome

Title	Progression-Free Survival (PFS) Determined by the Investigator
Description	PFS was defined as the time from randomization to first documented radiographical progressive disease (PD), as determined by the investigator using RECIST version 1.0, or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first (Kaplan-Meier method). For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of ≥1 new lesion. For non-target lesions, PD was defined as the appearance of ≥1 new lesion or unequivocal progression of existing lesions. Participants without PD or who had not died within 18 weeks of their last investigator-determined, progression-free tumor assessment were censored at the date of the last investigator tumor assessment; those with no post-baseline tumor assessment and who had not died within 18 weeks of baseline were censored at 1 day.
Time Frame	Tumor assessments every 9 weeks from randomization to investigator-determined PD or death from any cause, whichever occurred first (median [range] time on study in pertuzumab vs. placebo arms: 201.8 [0.7-520.0] weeks vs. 138.0 [0.4-514.7] weeks)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients.

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	402	406
Median (95% Confidence Interval) [Months]	18.7	12.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	PFS by Investigator - Stratified
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank (stratified)
	Comments	Stratified by prior treatment status and region.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.59 to 0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is comparing Pertuzumab arm with Placebo arm.

4. Secondary Outcome

Title	Objective Response Determined by an Independent Review Facility
Description	An objective response was defined as the percentage of participants with confirmed best overall response of complete response (CR) or partial response (PR) determined by an independent review facility (IRF) using RECIST v1.0 on two consecutive occasions ≥4 weeks apart. For target lesions, CR: disappearance of all target lesions; PR: ≥30% decrease in the sum of the longest diameter (LD) of target lesions (baseline sum LD as reference); PD: ≥20% increase in the sum of the LD of target lesions (smallest sum of the LD recorded as reference) or appearance of ≥1 new lesion; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase for PD. For non-target lesions, CR: disappearance of all non-target lesions; Incomplete/SD: persistence of ≥1 non-target lesions; PD: unequivocal progression of existing non-target lesions. 95% confidence intervals (CI) were calculated only for clinical responses using the Pearson-Clopper method.
Time Frame	Tumor assessments every 9 weeks from Baseline until IRF-determined progressive disease (PD), death, or first administration of next line of anti-cancer therapy (whichever occurred first), up to the primary completion date (up to 3 years, 3 months)

Outcome Measure Data

Analysis Population Description

ITT Population: All randomized participants; only participants with IRF-determined measurable disease at baseline (i.e., ≥1 target lesion) were included in the analysis.

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	343	336
Objective Response (CR + PR)	80.2	69.3
Complete Response (CR)	5.5	4.2
Partial Response (PR)	74.6	65.2
Stable Disease (SD)	14.6	20.8
Progressive Disease (PD)	3.8	8.3
Unable to Assess (UA)	0.6	0.6
Missing (No Assessment)	0.9	0.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	Difference in Objective Response (CR + PR) Between Arms
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	Mantel Haenszel
	Comments	Stratified by prior treatment status and region.
Method of Estimation	Estimation Parameter	Difference in Objective Response Rates
	Estimated Value	10.83
	Confidence Interval	(2-Sided) 95%; 4.2 to 17.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in the objective response rates between arms is calculated as Pertuzumab arm minus Placebo arm. The 95% CI was calculated using the Hauck-Anderson method.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	Odds Ratio for Objective Response (CR + PR)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.79
	Confidence Interval	(2-Sided) 95%; 1.26 to 2.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Duration of Objective Response Determined by an Independent Review Facility
Description	Duration of objective response (estimated using the Kaplan-Meier method) was defined as the time from the initial confirmed complete response (CR) or partial response (PR), the date of tumor assessment at which the CR/PR was first detected by the independent review facility (IRF) using RECIST version 1.0, until the date of IRF-determined progressive disease (PD), death from any cause within 18 weeks of the last tumor assessment, or first administration of next line of anti-cancer therapy (whichever occurred first). If the visit when the initial CR or PR was observed spanned multiple dates, the latest date was used. Only participants in the ITT analysis population with an IRF-determined objective response (CR or PR), observed prior to IRF-assessed PD, death or next line of anti-cancer therapy, were included in the analysis. Participants who did not progress or die after they had a confirmed response were censored at the date of their last IRF-evaluable tumor measurement.
Time Frame	From initial IRF-confirmed objective response until IRF-determined progressive disease (PD), death, or first administration of next line of anti-cancer therapy (whichever occurred first), up to the primary completion date (up to 3 years, 3 months)

Outcome Measure Data

Analysis Population Description

ITT Population: All randomized participants; only participants with IRF-determined measurable disease at baseline (i.e., ≥1 target lesion) that had an objective response were included in the analysis.

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	275	233
Median (95% Confidence Interval) [Weeks]	87.6	54.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.51 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Time to Symptom Progression
Description	Time to symptom progression was defined as the time from randomization to the first symptom progression as measured by the Functional Assessment of Cancer Therapy-for patients with Breast Cancer (FACT-B) questionnaire with the Trial Outcomes Index-Physical/Functional/Breast (TOI-PFB) subscale. The FACT-B TOI-PFB subscale contains 24 items from 3 subsections of the FACT-B questionnaire: Physical well-being, functional well-being, and additional concerns for breast cancer patients (breast cancer subscale [BCS]). All items in the questionnaire were rated by the patient on a 5-point scale ranging from 0 ("not at all") to 4 ("very much"). The total score ranged from 0 to 96. A higher score indicates better perceived quality of life. A positive change score from baseline indicates improvement. Symptom progression was defined as a decrease from baseline of 5 points or more.
Time Frame	Every 9 weeks from Baseline until investigator-determined progressive disease, up to the primary completion date (up to 3 years, 3 months)

Outcome Measure Data

Analysis Population Description

ITT population: All randomized participants; only female participants were included in the analysis.

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	402	404
Median (95% Confidence Interval) [Weeks]	18.4	18.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7161
	Comments	Stratified by prior treatment status and region.
	Method	Log Rank (stratified)
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is comparing Pertuzumab arm with Placebo arm.

7. Secondary Outcome

Title	Overall Number of Participants Who Experienced at Least One Adverse Event, Including Serious and Non-Serious Adverse Events, by Most Severe Intensity (According to NCI-CTCAE v3.0) During the Treatment Period
Description	Adverse event (AE) severity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 (NCI-CTCAE v3.0); 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. Only the most severe intensity was counted for multiple occurrences of the same AE in one participant. AEs reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for participants who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame	Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	396	408	50
At Least One Serious AE - All Grades	116 28.9%	160 39.4%	10 1.2%
At Least One Non-Serious AE - All Grades	386 96%	400 98.5%	45 5.6%
At Least One AE - All Grades	391 97.3%	408 100.5%	47 5.8%
At Least One AE - Grade 1	368 91.5%	386 95.1%	44 5.4%
At Least One AE - Grade 2	350 87.1%	383 94.3%	34 4.2%
At Least One AE - Grade 3	229 57%	264 65%	11 1.4%
At Least One AE - Grade 4	158 39.3%	167 41.1%	1 0.1%
At Least One AE - Grade 5	12 3%	8 2%	1 0.1%

8. Secondary Outcome

Title	Overall Number of Adverse Events by Severity (NCI-CTCAE v3.0 All Grades and Grades 3 to 5) Per 100 Patient-Years of Exposure During the Treatment Period
Description	Adverse event (AE) severity, including serious and non-serious AEs, was assessed according to the NCI-CTCAE version 3.0; if the AE was not specifically listed, the following grades of severity were used: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe; Grade 4 is life-threatening or disabling; and Grade 5 is death. Multiple occurrences of the same AE in 1 participant were counted multiple times. Only AEs that started during the overall study treatment period were included. The cutoff date for inclusion of events and for calculation of patient-years was the date of the most recent follow-up of the participant, defined as the last available date during the treatment period, excluding pre-treatment and safety follow-up data. Confidence intervals were calculated assuming the number of events followed a Poisson distribution. Data reported prior to the date of first crossover treatment were included under the Placebo arm for participants who crossed over from placebo to pertuzumab.
Time Frame	From Baseline to 42 days after the last dose of study treatment (total patient-years of exposure on study treatment in Placebo vs. Pertuzumab arms: 526.81 vs. 989.88 patient-years)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	396	408
Measure Adverse Events	9062	11908
All Grades	1720.2	1203.0
Grades 3 to 5	225.3	131.7

9. Secondary Outcome

Title	Cardiac-Related AEs to Monitor: Number of Participants Who Experienced at Least One Symptomatic Left Ventricular Dysfunction (LVD), Any LVD, or Serious AE Suggestive of Congestive Heart Failure by Severity During the Treatment Period
Description	Cardiac-related adverse events (AEs) to monitor during the study included investigator-assessed symptomatic left ventricular dysfunction (LVD), any LVD, or a serious adverse event (SAE) suggestive of congestive heart failure (CHF). All cardiac-related AEs were graded for severity according to NCI-CTCAE v3.0. Asymptomatic (Grades 1-2) and symptomatic (Grades 3-5) left ventricular systolic dysfunction (LVSD) both coded to the MedDRA preferred term LVD. Investigator-assessed events of symptomatic LVD were also graded for severity of symptoms according to Classes I (least severe) to IV (most severe) of the New York Heart Association (NYHA) Classification. SAEs suggestive of CHF were identified as serious events from the Standardized MedDRA Query (SMQ) (Wide) 'Cardiac Failure'. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame	Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	396	408	50
Symptomatic LVD(Investigator)-All NYHA Classes	7 1.7%	6 1.5%	1 0.1%
Symptomatic LVD(Investigator)-NYHA Classes III/IV	4 1%	4 1%	1 0.1%
Any LVD - All NCI-CTCAE Grades	34 8.5%	32 7.9%	3 0.4%
Any LVD - NCI-CTCAE Grade ≥3	13 3.2%	6 1.5%	2 0.2%
SAE Suggestive of CHF - All NCI-CTCAE Grades	8 2%	8 2%	1 0.1%
SAE Suggestive of CHF - NCI-CTCAE Grade ≥3	7 1.7%	7 1.7%	1 0.1%

10. Secondary Outcome

Title	Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period
Description	The clinical diagnoses listed in this table, excluding cardiac safety (summarized separately), were also selected as adverse events (AEs) to monitor based on clinical and nonclinical data for pertuzumab and the safety profile established for trastuzumab, monoclonal antibodies in general, and potential effects associated with HER receptor inhibition. Search strategies were defined by single or aggregate MedDRA Preferred Terms (PT) through Standardized MedDRA Queries (SMQ), where possible, or based on Roche AE Group Terms (AEGT). Diarrhoea AEs: High-Level Term (HLT) 'Diarrhoea (excl. infective)' and PT 'Diarrhoea infectious'. Leukopenic and Febrile Neutropenic Infections: AEs from 'Infections & Infestations' with start ≤14 days after start date of Grade ≥3 AEs in SMQ(narrow) 'Leukopenia' or PT 'Febrile neutropenia', respectively. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame	Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	396	408	50
Diarrhoea (HLT+PT) - All Grades	191 47.5%	280 69%	25 3.1%
Diarrhoea (HLT+PT) - Grade ≥3	20 5%	40 9.9%	1 0.1%
Rash (AEGT) - All Grades	155 38.6%	213 52.5%	18 2.2%
Rash (AEGT) - Grade ≥3	6 1.5%	15 3.7%	0 0%
Leukopenia (SMQ-narrow) - All Grades	231 57.5%	257 63.3%	1 0.1%
Leukopenia (SMQ-narrow) - Grade ≥3	211 52.5%	238 58.6%	0 0%
Leukopenic Infection (PTs) - All Grades	38 9.5%	53 13.1%	0 0%
Leukopenic Infection (PTs) - Grade ≥3	9 2.2%	18 4.4%	0 0%
Febrile Neutropenic Infection (PTs) - All Grades	3 0.7%	14 3.4%	0 0%
Febrile Neutropenic Infection (PTs) - Grade ≥3	1 0.2%	6 1.5%	0 0%
Anaphylaxis and Hypersensitivity (AEGT)-All Grades	37 9.2%	48 11.8%	1 0.1%
Anaphylaxis and Hypersensitivity (AEGT)-Grade ≥3	10 2.5%	9 2.2%	0 0%
Interstitial Lung Disease (SMQ-narrow) -All Grades	6 1.5%	10 2.5%	1 0.1%
Interstitial Lung Disease (SMQ-narrow) -Grade ≥3	2 0.5%	3 0.7%	0 0%
QT Prolongation (SMQ-wide) - All Grades	5 1.2%	16 3.9%	0 0%
QT Prolongation (SMQ-wide) - Grade ≥3	1 0.2%	7 1.7%	0 0%
Mucositis (AEGT) - All Grades	154 38.3%	208 51.2%	12 1.5%
Mucositis (AEGT) - Grade ≥3	8 2%	14 3.4%	0 0%
Drug-Related Hepatic Disorder(SMQ-wide)-All Grades	43 10.7%	47 11.6%	0 0%
Drug-Related Hepatic Disorder (SMQ-wide)-Grade ≥3	5 1.2%	8 2%	0 0%

11. Secondary Outcome

Title	Overall Number of Participants Who Experienced at Least One Adverse Event Leading to Discontinuation of Any or All Study Medication
Description	Participants could continue study treatment with pertuzumab/placebo plus trastuzumab when docetaxel was discontinued due to an adverse event (AE). Discontinuation of pertuzumab/placebo or trastuzumab due to an AE led to discontinuation of all study medication. The number of participants who discontinued any study medication due to an AE includes those who discontinued all study medication and those who discontinued docetaxel only and then continued on targeted therapy (note: some of these participants may have subsequently discontinued all treatment due to a separate AE). Multiple occurrences of the same adverse event in 1 participant was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for those who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame	Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	396	408	50
AE Leading to Discontinuation-Any Study Medication	114 28.4%	131 32.3%	5 0.6%
AE Leading to Discontinuation-All Study Medication	24 6%	39 9.6%	4 0.5%

12. Secondary Outcome

Title	Overall Number of Participants Who Experienced at Least One Adverse Event That Resulted in Interruption or Modification of Any Study Medication
Description	Pertuzumab, trastuzumab, and docetaxel administration could have been delayed to assess or treat adverse events (AEs). Docetaxel dose reduction was allowed for myelosuppression, hepatic dysfunction, and other toxicities. No dose reduction was allowed for pertuzumab or trastuzumab. Multiple occurrences of the same adverse event in one participant was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for participants who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks
Time Frame	Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	396	408	50
Count of Participants [Participants]	217 54%	265 65.3%	16 2%

13. Secondary Outcome

Title	Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period
Description	The post-treatment period was defined as the period following the treatment discontinuation visit. Only the following new adverse events (AEs) should have been reported during the post-treatment follow-up period: 1. Cardiac events (regardless of causality or seriousness) that started up to 1 year after the last dose, except for symptomatic left ventricular systolic dysfunction (regardless of causality) that started up to 3 years after the last dose; and 2. Treatment-related serious AEs, regardless of start date. AEs are listed by Medical Dictionary for Regulatory Activities, Version 21.1 (MedDRA v21.1) System Organ Class (SOC) and Preferred Term (PT); PTs fall under the SOC that is listed immediately above it in the table. Multiple occurrences of the same AE in one participant was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for participants who crossed over from placebo to pertuzumab.
Time Frame	From Day 43 after discontinuation of all study medication to end of post-treatment follow-up period (up to 3 years)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	396	408	50
Total with at Least One AE During Post-Treatment	18 4.5%	17 4.2%	3 0.4%
Cardiac Disorders (SOC)	8 2%	9 2.2%	1 0.1%
Left Ventricular Dysfunction (PT)	6 1.5%	5 1.2%	1 0.1%
Cardiac Failure (PT)	0 0%	2 0.5%	0 0%
Bundle Branch Block Left (PT)	0 0%	1 0.2%	0 0%
Cardiopulmonary Failure (PT)	1 0.2%	0 0%	0 0%
Myocardial Ischaemia (PT)	1 0.2%	0 0%	0 0%
Pericardial Effusion (PT)	0 0%	1 0.2%	0 0%
Prinzmetal Angina (PT)	1 0.2%	0 0%	0 0%
General Disorders & Admin. Site Conditions (SOC)	3 0.7%	2 0.5%	0 0%
Oedema Peripheral (PT)	2 0.5%	1 0.2%	0 0%
Asthenia (PT)	1 0.2%	0 0%	0 0%
Influenza Like Illness (PT)	0 0%	1 0.2%	0 0%
Infections & Infestations (SOC)	0 0%	0 0%	2 0.2%
Influenza (PT)	0 0%	0 0%	1 0.1%
Viral Infection (PT)	0 0%	0 0%	1 0.1%
Abscess Limb (PT)	0 0%	1 0.2%	0 0%
Nasopharyngitis (PT)	1 0.2%	0 0%	0 0%
Subcutaneous Abscess (PT)	0 0%	1 0.2%	0 0%
Musculoskeletal & Connective Tissue Disorders(SOC)	0 0%	0 0%	1 0.1%
Back Pain (PT)	0 0%	0 0%	1 0.1%
Pain in Extremity (PT)	1 0.2%	0 0%	0 0%
Nervous System Disorders (SOC)	2 0.5%	2 0.5%	0 0%
Neuropathy Peripheral (PT)	1 0.2%	1 0.2%	0 0%
Cognitive Disorder (PT)	1 0.2%	0 0%	0 0%
Dizziness (PT)	0 0%	1 0.2%	0 0%
Headache (PT)	0 0%	1 0.2%	0 0%
Respiratory, Thoracic & Mediastinal Disorders(SOC)	2 0.5%	1 0.2%	0 0%
Cough (PT)	1 0.2%	0 0%	0 0%
Dyspnoea (PT)	1 0.2%	0 0%	0 0%
Rhinitis Allergic (PT)	0 0%	1 0.2%	0 0%
Skin & Subcutaneous Tissue Disorders (SOC)	1 0.2%	2 0.5%	0 0%
Erythema (PT)	0 0%	1 0.2%	0 0%
Nail Disorder (PT)	1 0.2%	0 0%	0 0%
Rash Macular (PT)	0 0%	1 0.2%	0 0%
Blood & Lymphatic System Disorders (SOC)	1 0.2%	1 0.2%	0 0%
Febrile Neutropenia (PT)	1 0.2%	0 0%	0 0%
Leukopenia (PT)	0 0%	1 0.2%	0 0%
Gastrointestinal Disorders (SOC)	0 0%	2 0.5%	0 0%
Diarrhoea (PT)	0 0%	1 0.2%	0 0%
Stomatitis (PT)	0 0%	1 0.2%	0 0%
Endocrine Disorders (SOC)	1 0.2%	0 0%	0 0%
Thyroid Mass (PT)	1 0.2%	0 0%	0 0%
Eye Disorders (SOC)	1 0.2%	0 0%	0 0%
Retinal Detachment (PT)	1 0.2%	0 0%	0 0%
Immune System Disorders (SOC)	0 0%	1 0.2%	0 0%
Iodine Allergy (PT)	0 0%	1 0.2%	0 0%
Investigations (SOC)	1 0.2%	0 0%	0 0%
Aspartate Aminotransferase Increased (PT)	1 0.2%	0 0%	0 0%
Renal & Urinary Disorders (SOC)	0 0%	1 0.2%	0 0%
Dysuria (PT)	0 0%	1 0.2%	0 0%
Reproductive System & Breast Disorders (SOC)	0 0%	1 0.2%	0 0%
Breast Induration (PT)	0 0%	1 0.2%	0 0%
Vascular Disorders (SOC)	0 0%	1 0.2%	0 0%
Venous Thrombosis (PT)	0 0%	1 0.2%	0 0%

14. Secondary Outcome

Title	Number of Participants by Categories for the Maximum Absolute Decrease From Baseline in LVEF Value During the Treatment Period
Description	All participants were required to have an left ventricular ejection fraction (LVEF) ≥50% at baseline, as measured by echocardiogram (preferred) or multiple-gated acquisition (MUGA) scan. The same method of LVEF assessment and the same institution/facility used at baseline was used throughout the study, to the extent possible. The baseline value was defined as the last valid value recorded during the pre-treatment period before or on study Day 1. The maximum absolute decrease in LVEF value was defined as the lowest post-baseline value up to the end of the overall study treatment period. Data reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for participants who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame	Every 9 weeks from the date of randomization until Treatment Discontinuation Visit (see Description for time on study treatment per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication. Only participants with evaluable LVEF assessments during the overall study treatment period were included in the analysis.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	396	408	50
LVEF Increase/No Change/Decrease FromBL <10%Points	252 62.7%	249 61.3%	30 3.7%
LVEF <50% and Decrease From BL ≥10% to <15% Points	9 2.2%	7 1.7%	0 0%
LVEF <50% and Decrease From BL ≥15% Points	19 4.7%	21 5.2%	3 0.4%
LVEF ≥50% and Decrease From BL ≥10% Points	95 23.6%	115 28.3%	15 1.9%
No Baseline (BL) LVEF Value	3 0.7%	2 0.5%	1 0.1%

15. Secondary Outcome

Title	Baseline LVEF Value and Change in LVEF From Baseline at Maximum Absolute Decrease Value During the Treatment Period
Description	All participants were required to have a left ventricular ejection fraction (LVEF) ≥50% at baseline, as measured by echocardiogram (preferred) or multiple-gated acquisition (MUGA) scan. The same method of LVEF assessment and the same institution/facility used at baseline was used throughout the study, to the extent possible. The baseline value was defined as the last valid value recorded during the pre-treatment period before or on study Day 1. The maximum absolute decrease in LVEF value was defined as the lowest post-baseline value up to the end of the overall study treatment period. Only data reported prior to the date of first crossover treatment were included for participants who crossed over from placebo to pertuzumab.
Time Frame	Every 9 weeks from the date of randomization until Treatment Discontinuation Visit (median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication. Only participants with evaluable LVEF assessments at baseline (BL) or at BL and post-BL (for change in LVEF from BL at max. decrease) were included in the analyses.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	396	408
Baseline (BL) LVEF Value	65.6 (6.51)	64.8 (6.71)
Change in LVEF From BL at Maximum Decrease Value	-7.3 (7.15)	-7.5 (7.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	Wilcoxon Test of Maximum Decrease in LVEF From BL
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7174
	Comments
	Method	Wilcoxon Rank Sum Test
	Comments

16. Secondary Outcome

Title	Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period
Description	Clinical laboratory tests for blood biochemistry parameters were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest grade according to NCI-CTCAE v3.0. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks. ALP = alkaline phosphatase; GGT = gamma-glutamyl transferase; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase
Time Frame	On Day 1 of every treatment cycle (1 cycle is 21 days) until Treatment Discontinuation Visit (see Description for time on study treatment per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication. Only participants with at least one valid laboratory value for any given parameter during the overall study treatment period were included in the analysis.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	396	408	50
Albumin (g/L) - Low, Any Grade (Gr.)	163 40.5%	196 48.3%	15 1.9%
Albumin (g/L) - Low, Gr. 1	113 28.1%	132 32.5%	10 1.2%
Albumin (g/L) - Low, Gr. 2	46 11.4%	58 14.3%	4 0.5%
Albumin (g/L) - Low, Gr. 3	4 1%	6 1.5%	1 0.1%
Albumin (g/L) - Low, Gr. 4	0 0%	0 0%	0 0%
ALP (U/L) - High, Any Gr.	184 45.8%	210 51.7%	17 2.1%
ALP (U/L) - High, Gr. 1	158 39.3%	177 43.6%	17 2.1%
ALP (U/L) - High, Gr. 2	19 4.7%	24 5.9%	0 0%
ALP (U/L) - High, Gr. 3	7 1.7%	9 2.2%	0 0%
ALP (U/L) - High, Gr. 4	0 0%	0 0%	0 0%
Calcium (mmol/L) - Low, Any Gr.	156 38.8%	203 50%	14 1.7%
Calcium (mmol/L) - Low, Gr. 1	107 26.6%	139 34.2%	11 1.4%
Calcium (mmol/L) - Low, Gr. 2	45 11.2%	49 12.1%	0 0%
Calcium (mmol/L) - Low, Gr. 3	3 0.7%	7 1.7%	1 0.1%
Calcium (mmol/L) - Low, Gr. 4	1 0.2%	8 2%	2 0.2%
Calcium (mmol/L) - High, Any Gr.	54 13.4%	79 19.5%	12 1.5%
Calcium (mmol/L) - High, Gr. 1	50 12.4%	65 16%	7 0.9%
Calcium (mmol/L) - High, Gr. 2	0 0%	2 0.5%	1 0.1%
Calcium (mmol/L) - High, Gr. 3	3 0.7%	2 0.5%	0 0%
Calcium (mmol/L) - High, Gr. 4	1 0.2%	10 2.5%	4 0.5%
Creatinine (umol/L) - High, Any Gr.	317 78.9%	346 85.2%	38 4.7%
Creatinine (umol/L) - High, Gr. 1	271 67.4%	279 68.7%	27 3.3%
Creatinine (umol/L) - High, Gr. 2	44 10.9%	54 13.3%	9 1.1%
Creatinine (umol/L) - High, Gr. 3	2 0.5%	6 1.5%	0 0%
Creatinine (umol/L) - High, Gr. 4	0 0%	7 1.7%	2 0.2%
Fasting Glucose (mmol/L) - Low, Any Gr.	42 10.4%	75 18.5%	6 0.7%
Fasting Glucose (mmol/L) - Low, Gr. 1	32 8%	61 15%	4 0.5%
Fasting Glucose (mmol/L) - Low, Gr. 2	9 2.2%	9 2.2%	0 0%
Fasting Glucose (mmol/L) - Low, Gr. 3	1 0.2%	2 0.5%	0 0%
Fasting Glucose (mmol/L) - Low, Gr. 4	0 0%	3 0.7%	2 0.2%
Fasting Glucose (mmol/L) - High, Any Gr.	271 67.4%	299 73.6%	34 4.2%
Fasting Glucose (mmol/L) - High, Gr. 1	168 41.8%	192 47.3%	26 3.2%
Fasting Glucose (mmol/L) - High, Gr. 2	83 20.6%	78 19.2%	8 1%
Fasting Glucose (mmol/L) - High, Gr. 3	20 5%	26 6.4%	0 0%
Fasting Glucose (mmol/L) - High, Gr. 4	0 0%	3 0.7%	0 0%
GGT (U/L) - High, Any Gr.	209 52%	225 55.4%	14 1.7%
GGT (U/L) - High, Gr. 1	133 33.1%	144 35.5%	9 1.1%
GGT (U/L) - High, Gr. 2	41 10.2%	52 12.8%	4 0.5%
GGT (U/L) - High, Gr. 3	30 7.5%	27 6.7%	1 0.1%
GGT (U/L) - High, Gr. 4	5 1.2%	2 0.5%	0 0%
Magnesium (mmol/L) - Low, Any Gr.	79 19.7%	117 28.8%	8 1%
Magnesium (mmol/L) - Low, Gr. 1	71 17.7%	98 24.1%	6 0.7%
Magnesium (mmol/L) - Low, Gr. 2	7 1.7%	13 3.2%	0 0%
Magnesium (mmol/L) - Low, Gr. 3	1 0.2%	3 0.7%	0 0%
Magnesium (mmol/L) - Low, Gr. 4	0 0%	3 0.7%	2 0.2%
Magnesium (mmol/L) - High, Any Gr.	76 18.9%	105 25.9%	16 2%
Magnesium (mmol/L) - High, Gr. 1	58 14.4%	80 19.7%	11 1.4%
Magnesium (mmol/L) - High, Gr. 2	0 0%	0 0%	0 0%
Magnesium (mmol/L) - High, Gr. 3	18 4.5%	22 5.4%	4 0.5%
Magnesium (mmol/L) - High, Gr. 4	0 0%	3 0.7%	1 0.1%
Potassium (mmol/L) - Low, Any Gr.	80 19.9%	144 35.5%	11 1.4%
Potassium (mmol/L) - Low, Gr. 1	0 0%	0 0%	0 0%
Potassium (mmol/L) - Low, Gr. 2	68 16.9%	118 29.1%	8 1%
Potassium (mmol/L) - Low, Gr. 3	10 2.5%	18 4.4%	2 0.2%
Potassium (mmol/L) - Low, Gr. 4	2 0.5%	8 2%	1 0.1%
Potassium (mmol/L) - High, Any Gr.	67 16.7%	78 19.2%	13 1.6%
Potassium (mmol/L) - High, Gr. 1	49 12.2%	55 13.5%	11 1.4%
Potassium (mmol/L) - High, Gr. 2	15 3.7%	17 4.2%	2 0.2%
Potassium (mmol/L) - High, Gr. 3	3 0.7%	6 1.5%	0 0%
Potassium (mmol/L) - High, Gr. 4	0 0%	0 0%	0 0%
SGOT (U/L) - High, Any Gr.	184 45.8%	193 47.5%	17 2.1%
SGOT (U/L) - High, Gr. 1	169 42%	170 41.9%	15 1.9%
SGOT (U/L) - High, Gr. 2	11 2.7%	12 3%	2 0.2%
SGOT (U/L) - High, Gr. 3	4 1%	10 2.5%	0 0%
SGOT (U/L) - High, Gr. 4	0 0%	1 0.2%	0 0%
SGPT (U/L) - High, Any Gr.	195 48.5%	209 51.5%	19 2.4%
SGPT (U/L) - High, Gr. 1	172 42.8%	175 43.1%	17 2.1%
SGPT (U/L) - High, Gr. 2	18 4.5%	19 4.7%	2 0.2%
SGPT (U/L) - High, Gr. 3	5 1.2%	14 3.4%	0 0%
SGPT (U/L) - High, Gr. 4	0 0%	1 0.2%	0 0%
Sodium (mmol/L) - Low, Any Gr.	109 27.1%	135 33.3%	25 3.1%
Sodium (mmol/L) - Low, Gr. 1	87 21.6%	121 29.8%	22 2.7%
Sodium (mmol/L) - Low, Gr. 2	0 0%	0 0%	0 0%
Sodium (mmol/L) - Low, Gr. 3	21 5.2%	12 3%	1 0.1%
Sodium (mmol/L) - Low, Gr. 4	1 0.2%	2 0.5%	2 0.2%
Sodium (mmol/L) - High, Any Gr.	76 18.9%	103 25.4%	9 1.1%
Sodium (mmol/L) - High, Gr. 1	71 17.7%	91 22.4%	7 0.9%
Sodium (mmol/L) - High, Gr. 2	4 1%	9 2.2%	2 0.2%
Sodium (mmol/L) - High, Gr. 3	1 0.2%	2 0.5%	0 0%
Sodium (mmol/L) - High, Gr. 4	0 0%	1 0.2%	0 0%
Total Bilirubin (umol/L) - High, Any Gr.	35 8.7%	57 14%	7 0.9%
Total Bilirubin (umol/L) - High, Gr. 1	26 6.5%	44 10.8%	6 0.7%
Total Bilirubin (umol/L) - High, Gr. 2	7 1.7%	9 2.2%	0 0%
Total Bilirubin (umol/L) - High, Gr. 3	2 0.5%	2 0.5%	0 0%
Total Bilirubin (umol/L) - High, Gr. 4	0 0%	2 0.5%	1 0.1%
Uric Acid (umol/L) - High, Any Gr.	118 29.4%	113 27.8%	15 1.9%
Uric Acid (umol/L) - High, Gr. 1	0 0%	0 0%	0 0%
Uric Acid (umol/L) - High, Gr. 2	0 0%	0 0%	0 0%
Uric Acid (umol/L) - High, Gr. 3	116 28.9%	98 24.1%	10 1.2%
Uric Acid (umol/L) - High, Gr. 4	2 0.5%	15 3.7%	5 0.6%

17. Secondary Outcome

Title	Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period
Description	Clinical laboratory tests for hematology parameters were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest grade according to NCI-CTCAE v3.0. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks. INR = International Normalized Ratio; PTT = partial thromboplastin time; WBC = white blood cell
Time Frame	On Day 1 (and Day 8 for some measures) of every treatment cycle (1 cycle is 21 days) until Treatment Discontinuation Visit (see Description for time on study treatment per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication. Only participants with at least one valid laboratory value for any given parameter during the overall study treatment period were included in the analysis.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Measure Participants	396	408	50
Hemoglobin (g/L) - Low, Any Grade (Gr.)	350 87.1%	372 91.6%	20 2.5%
Hemoglobin (g/L) - Low, Gr. 1	202 50.2%	186 45.8%	9 1.1%
Hemoglobin (g/L) - Low, Gr. 2	127 31.6%	161 39.7%	6 0.7%
Hemoglobin (g/L) - Low, Gr. 3	21 5.2%	25 6.2%	5 0.6%
Hemoglobin (g/L) - Low, Gr. 4	0 0%	0 0%	0 0%
Hemoglobin (g/L) - High, Any Gr.	10 2.5%	23 5.7%	4 0.5%
Hemoglobin (g/L) - High, Gr. 1	9 2.2%	20 4.9%	2 0.2%
Hemoglobin (g/L) - High, Gr. 2	1 0.2%	2 0.5%	0 0%
Hemoglobin (g/L) - High, Gr. 3	0 0%	1 0.2%	2 0.2%
Hemoglobin (g/L) - High, Gr. 4	0 0%	0 0%	0 0%
Lymphocytes (10^9/L) - Low, Any Gr.	259 64.4%	276 68%	8 1%
Lymphocytes (10^9/L) - Low, Gr. 1	36 9%	39 9.6%	0 0%
Lymphocytes (10^9/L) - Low, Gr. 2	128 31.8%	136 33.5%	4 0.5%
Lymphocytes (10^9/L) - Low, Gr. 3	64 15.9%	69 17%	3 0.4%
Lymphocytes (10^9/L) - Low, Gr. 4	31 7.7%	32 7.9%	1 0.1%
Lymphocytes (10^9/L)- High, Any Gr.	58 14.4%	72 17.7%	9 1.1%
Lymphocytes (10^9/L)- High, Gr. 1	0 0%	0 0%	0 0%
Lymphocytes (10^9/L)- High, Gr. 2	49 12.2%	57 14%	6 0.7%
Lymphocytes (10^9/L)- High, Gr. 3	9 2.2%	15 3.7%	3 0.4%
Lymphocytes (10^9/L)- High, Gr. 4	0 0%	0 0%	0 0%
Neutrophils (10^9/L)- Low, Any Gr.	349 86.8%	371 91.4%	2 0.2%
Neutrophils (10^9/L)- Low, Gr. 1	7 1.7%	4 1%	0 0%
Neutrophils (10^9/L)- Low, Gr. 2	25 6.2%	34 8.4%	0 0%
Neutrophils (10^9/L)- Low, Gr. 3	81 20.1%	99 24.4%	0 0%
Neutrophils (10^9/L)- Low, Gr. 4	236 58.7%	234 57.6%	2 0.2%
PTT (sec) - High, Any Gr.	6 1.5%	9 2.2%	1 0.1%
PTT (sec) - High, Gr. 1	5 1.2%	2 0.5%	1 0.1%
PTT (sec) - High, Gr. 2	0 0%	4 1%	0 0%
PTT (sec) - High, Gr. 3	1 0.2%	3 0.7%	0 0%
PTT (sec) - High, Gr. 4	0 0%	0 0%	0 0%
Platelets (10^9/L) - Low, Any Gr.	82 20.4%	92 22.7%	13 1.6%
Platelets (10^9/L) - Low, Gr. 1	75 18.7%	78 19.2%	11 1.4%
Platelets (10^9/L) - Low, Gr. 2	5 1.2%	5 1.2%	0 0%
Platelets (10^9/L) - Low, Gr. 3	2 0.5%	3 0.7%	0 0%
Platelets (10^9/L) - Low, Gr. 4	0 0%	6 1.5%	2 0.2%
Prothrombin Time (INR) - High, Any Gr.	135 33.6%	157 38.7%	11 1.4%
Prothrombin Time (INR) - High, Gr. 1	127 31.6%	136 33.5%	9 1.1%
Prothrombin Time (INR) - High, Gr. 2	3 0.7%	6 1.5%	0 0%
Prothrombin Time (INR) - High, Gr. 3	5 1.2%	15 3.7%	2 0.2%
Prothrombin Time (INR) - High, Gr. 4	0 0%	0 0%	0 0%
WBC (10^9/L) - Low, Any Gr.	366 91%	387 95.3%	5 0.6%
WBC (10^9/L) - Low, Gr. 1	36 9%	34 8.4%	1 0.1%
WBC (10^9/L) - Low, Gr. 2	92 22.9%	92 22.7%	3 0.4%
WBC (10^9/L) - Low, Gr. 3	186 46.3%	206 50.7%	0 0%
WBC (10^9/L) - Low, Gr. 4	52 12.9%	55 13.5%	1 0.1%
WBC (10^9/L) - High, Any Gr.	0 0%	3 0.7%	1 0.1%
WBC (10^9/L) - High, Gr. 1	0 0%	0 0%	0 0%
WBC (10^9/L) - High, Gr. 2	0 0%	0 0%	0 0%
WBC (10^9/L) - High, Gr. 3	0 0%	3 0.7%	1 0.1%
WBC (10^9/L) - High, Gr. 4	0 0%	0 0%	0 0%

Adverse Events

Time Frame	From first treatment dose (12-Feb-2008) through to end of study (23-Nov-2018) for a total safety analysis timeframe of 10 years, 9.5 months.
Adverse Event Reporting Description	Of enrolled participants (Pertuzumab [Ptz]: N=402, Placebo [Pla]: N=406), 2 in each arm received no treatment (total of 4), 9 in Pla arm received at least 1 dose of Ptz, and 1 in Ptz arm received Pla at every cycle; resulting in a Safety Population of Ptz: N=408 (402-2+9-1), Pla: N=396 (406-2-9+1), and 50 participants in Pla arm crossed over to Ptz.
Arm/Group Title	Placebo + Trastuzumab + Docetaxel		Pertuzumab + Trastuzumab + Docetaxel		Crossover From Placebo to Pertuzumab
Arm/Group Description	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.		This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.		Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
All Cause Mortality
	Placebo + Trastuzumab + Docetaxel		Pertuzumab + Trastuzumab + Docetaxel		Crossover From Placebo to Pertuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	261/396 (65.9%)		238/408 (58.3%)		14/50 (28%)
Serious Adverse Events
	Placebo + Trastuzumab + Docetaxel		Pertuzumab + Trastuzumab + Docetaxel		Crossover From Placebo to Pertuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	116/396 (29.3%)		160/408 (39.2%)		10/50 (20%)
Blood and lymphatic system disorders
Anaemia	3/396 (0.8%)	3	3/408 (0.7%)	4	1/50 (2%)	1
Febrile neutropenia	20/396 (5.1%)	23	46/408 (11.3%)	48	0/50 (0%)	0
Granulocytopenia	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Leukopenia	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Neutropenia	19/396 (4.8%)	20	18/408 (4.4%)	23	0/50 (0%)	0
Cardiac disorders
Atrial fibrillation	3/396 (0.8%)	3	0/408 (0%)	0	0/50 (0%)	0
Cardiac failure congestive	0/396 (0%)	0	2/408 (0.5%)	2	0/50 (0%)	0
Coronary artery disease	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Left ventricular dysfunction	7/396 (1.8%)	7	6/408 (1.5%)	6	1/50 (2%)	1
Myocardial infarction	3/396 (0.8%)	3	0/408 (0%)	0	0/50 (0%)	0
Myocardial ischaemia	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Ventricular fibrillation	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Ear and labyrinth disorders
Vertigo	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Eye disorders
Cataract	0/396 (0%)	0	2/408 (0.5%)	2	1/50 (2%)	1
Gastrointestinal disorders
Abdominal pain	1/396 (0.3%)	2	0/408 (0%)	0	0/50 (0%)	0
Colitis	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Constipation	2/396 (0.5%)	3	0/408 (0%)	0	0/50 (0%)	0
Diarrhoea	5/396 (1.3%)	5	13/408 (3.2%)	16	1/50 (2%)	1
Duodenal ulcer	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Duodenal ulcer haemorrhage	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Enteritis	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Gastrointestinal haemorrhage	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Haemorrhoidal haemorrhage	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Haemorrhoids	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Intestinal ischaemia	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Intestinal obstruction	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Intestinal perforation	2/396 (0.5%)	2	0/408 (0%)	0	0/50 (0%)	0
Lower gastrointestinal haemorrhage	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Nausea	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Oesophagitis	0/396 (0%)	0	2/408 (0.5%)	2	0/50 (0%)	0
Rectal haemorrhage	1/396 (0.3%)	1	1/408 (0.2%)	1	0/50 (0%)	0
Upper gastrointestinal haemorrhage	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Vomiting	1/396 (0.3%)	1	2/408 (0.5%)	2	0/50 (0%)	0
Volvulus	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Small intestinal obstruction	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
General disorders
Drowning	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Asthenia	0/396 (0%)	0	2/408 (0.5%)	2	0/50 (0%)	0
Chest pain	2/396 (0.5%)	2	1/408 (0.2%)	1	0/50 (0%)	0
Death	0/396 (0%)	0	1/408 (0.2%)	1	1/50 (2%)	1
Fatigue	1/396 (0.3%)	1	2/408 (0.5%)	2	0/50 (0%)	0
General physical health deterioration	2/396 (0.5%)	2	0/408 (0%)	0	0/50 (0%)	0
Influenza like illness	0/396 (0%)	0	2/408 (0.5%)	2	0/50 (0%)	0
Mucosal inflammation	1/396 (0.3%)	1	1/408 (0.2%)	1	0/50 (0%)	0
Pyrexia	3/396 (0.8%)	3	6/408 (1.5%)	6	2/50 (4%)	2
Hepatobiliary disorders
Cholecystitis acute	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Cholelithiasis	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Hepatic failure	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Immune system disorders
Anaphylactic reaction	1/396 (0.3%)	1	1/408 (0.2%)	1	0/50 (0%)	0
Drug hypersensitivity	3/396 (0.8%)	3	3/408 (0.7%)	3	0/50 (0%)	0
Hypersensitivity	0/396 (0%)	0	3/408 (0.7%)	3	0/50 (0%)	0
Infections and infestations
Acute sinusitis	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Anal abscess	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Appendicitis	0/396 (0%)	0	2/408 (0.5%)	2	0/50 (0%)	0
Breast abscess	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Breast cellulitis	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Campylobacter gastroenteritis	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Catheter site infection	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Cellulitis	2/396 (0.5%)	2	10/408 (2.5%)	12	0/50 (0%)	0
Cellulitis gangrenous	0/396 (0%)	0	0/408 (0%)	0	1/50 (2%)	1
Clostridium difficile colitis	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Coccidioidomycosis	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Vascular device infection	1/396 (0.3%)	1	2/408 (0.5%)	2	0/50 (0%)	0
Diarrhoea infectious	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Erysipelas	0/396 (0%)	0	2/408 (0.5%)	2	0/50 (0%)	0
Gastroenteritis	2/396 (0.5%)	3	2/408 (0.5%)	2	0/50 (0%)	0
Gastrointestinal infection	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
H1N1 influenza	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Herpes zoster	3/396 (0.8%)	3	1/408 (0.2%)	1	0/50 (0%)	0
Infection	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Lower respiratory tract infection	0/396 (0%)	0	4/408 (1%)	4	0/50 (0%)	0
Lymph node tuberculosis	0/396 (0%)	0	0/408 (0%)	0	1/50 (2%)	1
Neutropenic infection	1/396 (0.3%)	1	4/408 (1%)	4	0/50 (0%)	0
Neutropenic sepsis	2/396 (0.5%)	2	0/408 (0%)	0	0/50 (0%)	0
Onychomycosis	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Oral candidiasis	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Osteomyelitis	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Osteomyelitis chronic	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Pharyngitis	0/396 (0%)	0	2/408 (0.5%)	2	0/50 (0%)	0
Pneumonia	11/396 (2.8%)	11	7/408 (1.7%)	7	1/50 (2%)	1
Pneumonia staphylococcal	0/396 (0%)		1/408 (0.2%)		0/50 (0%)
Postoperative wound infection	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Pyelonephritis acute	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Rash pustular	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Respiratory tract infection	1/396 (0.3%)	1	1/408 (0.2%)	1	0/50 (0%)	0
Respiratory tract infection viral	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Sepsis	3/396 (0.8%)	3	1/408 (0.2%)	1	0/50 (0%)	0
Sepsis syndrome	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Septic shock	1/396 (0.3%)	1	1/408 (0.2%)	1	0/50 (0%)	0
Skin infection	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Soft tissue infection	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Upper respiratory tract infection	0/396 (0%)	0	2/408 (0.5%)	2	0/50 (0%)	0
Urinary tract infection	1/396 (0.3%)	1	3/408 (0.7%)	3	0/50 (0%)	0
Urosepsis	0/396 (0%)	0	2/408 (0.5%)	2	0/50 (0%)	0
Viral infection	2/396 (0.5%)	2	0/408 (0%)	0	0/50 (0%)	0
Wound infection	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Wound infection staphylococcal	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Acute hepatitis B	0/396 (0%)	0	0/408 (0%)	0	1/50 (2%)	1
Pyelonephritis	0/396 (0%)	0	0/408 (0%)	0	1/50 (2%)	1
Groin abscess	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Pharyngotonsillitis	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Urinary tract infection bacterial	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Injury, poisoning and procedural complications
Compression fracture	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Contusion	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Femur fracture	1/396 (0.3%)	1	3/408 (0.7%)	3	0/50 (0%)	0
Fracture	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Post procedural discomfort	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Scapula fracture	0/396 (0%)		1/408 (0.2%)		0/50 (0%)	0
Tendon injury	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Thermal burn	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Tibia fracture	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Hip fracture	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Tendon rupture	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Upper limb fracture	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Investigations
Blood electrolytes abnormal	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Blood glucose increased	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Ejection fraction decreased	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Dehydration	2/396 (0.5%)	2	1/408 (0.2%)	1	1/50 (2%)	1
Diabetes mellitus	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Fluid retention	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Hyperglycaemia	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Hypoglycaemia	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/396 (0.3%)	1	2/408 (0.5%)	2	0/50 (0%)	0
Mobility decreased	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Muscular weakness	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Myalgia	1/396 (0.3%)	1	1/408 (0.2%)	1	0/50 (0%)	0
Neck pain	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Osteonecrosis of jaw	0/396 (0%)	0	2/408 (0.5%)	2	0/50 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Colon cancer	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Endometrial cancer	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Glioblastoma multiforme	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Ocular neoplasm	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Pituitary tumour benign	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Tumour haemorrhage	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Uterine leiomyoma	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Nervous system disorders
Cerebrovascular accident	1/396 (0.3%)	1	1/408 (0.2%)	1	0/50 (0%)	0
Seizure	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Monoparesis	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Peripheral sensorimotor neuropathy	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Somnolence	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Spinal cord compression	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Syncope	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Facial paralysis	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Cerebral haematoma	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Headache	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Loss of consciousness	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Psychiatric disorders
Suicide attempt	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Renal and urinary disorders
Haematuria	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Nephrolithiasis	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Renal failure	1/396 (0.3%)	1	1/408 (0.2%)	1	0/50 (0%)	0
Chronic kidney disease	0/396 (0%)	0	0/408 (0%)	0	1/50 (2%)	1
Acute kidney injury	2/396 (0.5%)	2	2/408 (0.5%)	2	0/50 (0%)	0
Reproductive system and breast disorders
Breast haemorrhage	1/396 (0.3%)	2	0/408 (0%)	0	0/50 (0%)	0
Metrorrhagia	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Vaginal haemorrhage	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	1/396 (0.3%)	6	0/408 (0%)	0	0/50 (0%)	0
Dyspnoea	2/396 (0.5%)	2	2/408 (0.5%)	2	0/50 (0%)	0
Haemoptysis	0/396 (0%)	0	1/408 (0.2%)	2	0/50 (0%)	0
Interstitial lung disease	0/396 (0%)	0	2/408 (0.5%)	2	0/50 (0%)	0
Pleural effusion	4/396 (1%)	5	2/408 (0.5%)	5	0/50 (0%)	0
Pneumonia aspiration	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Pneumonitis	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Pneumothorax	1/396 (0.3%)	1	1/408 (0.2%)	1	0/50 (0%)	0
Pulmonary embolism	0/396 (0%)	0	6/408 (1.5%)	6	0/50 (0%)	0
Respiratory failure	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Hypoxia	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis allergic	0/396 (0%)	0	1/408 (0.2%)	2	0/50 (0%)	0
Drug eruption	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Rash maculo-papular	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Surgical and medical procedures
Abortion induced	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Vascular disorders
Aortic stenosis	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Deep vein thrombosis	0/396 (0%)	0	3/408 (0.7%)	3	0/50 (0%)	0
Vena cava thrombosis	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Hypertension	1/396 (0.3%)	1	1/408 (0.2%)	1	0/50 (0%)	0
Hypertensive crisis	1/396 (0.3%)	1	0/408 (0%)	0	0/50 (0%)	0
Hypotension	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Venous thrombosis limb	0/396 (0%)	0	1/408 (0.2%)	1	0/50 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo + Trastuzumab + Docetaxel		Pertuzumab + Trastuzumab + Docetaxel		Crossover From Placebo to Pertuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	386/396 (97.5%)		400/408 (98%)		45/50 (90%)
Blood and lymphatic system disorders
Neutropenia	191/396 (48.2%)	797	209/408 (51.2%)	849	1/50 (2%)	1
Anaemia	77/396 (19.4%)	143	100/408 (24.5%)	151	6/50 (12%)	15
Leukopenia	82/396 (20.7%)	344	75/408 (18.4%)	288	0/50 (0%)	0
Cardiac disorders
Left ventricular dysfunction	27/396 (6.8%)	33	27/408 (6.6%)	43	3/50 (6%)	9
Eye disorders
Lacrimation increased	55/396 (13.9%)	63	60/408 (14.7%)	74	0/50 (0%)	0
Dry eye	8/396 (2%)	8	24/408 (5.9%)	27	2/50 (4%)	2
Cataract	1/396 (0.3%)	1	7/408 (1.7%)	8	3/50 (6%)	3
Gastrointestinal disorders
Diarrhoea	191/396 (48.2%)	428	277/408 (67.9%)	989	25/50 (50%)	155
Nausea	168/396 (42.4%)	359	184/408 (45.1%)	394	4/50 (8%)	7
Vomiting	96/396 (24.2%)	150	110/408 (27%)	184	5/50 (10%)	7
Constipation	100/396 (25.3%)	179	69/408 (16.9%)	135	4/50 (8%)	6
Stomatitis	63/396 (15.9%)	138	82/408 (20.1%)	167	6/50 (12%)	13
Abdominal pain	50/396 (12.6%)	66	64/408 (15.7%)	86	2/50 (4%)	2
Dyspepsia	48/396 (12.1%)	73	55/408 (13.5%)	80	3/50 (6%)	8
Abdominal pain upper	43/396 (10.9%)	54	44/408 (10.8%)	69	2/50 (4%)	2
Gastritis	7/396 (1.8%)	8	16/408 (3.9%)	20	3/50 (6%)	3
General disorders
Fatigue	148/396 (37.4%)	291	156/408 (38.2%)	320	5/50 (10%)	16
Asthenia	122/396 (30.8%)	268	114/408 (27.9%)	265	3/50 (6%)	3
Oedema peripheral	111/396 (28%)	163	102/408 (25%)	141	1/50 (2%)	1
Mucosal inflammation	78/396 (19.7%)	111	111/408 (27.2%)	185	1/50 (2%)	1
Pyrexia	72/396 (18.2%)	94	81/408 (19.9%)	138	3/50 (6%)	6
Oedema	49/396 (12.4%)	76	49/408 (12%)	84	1/50 (2%)	1
Chills	15/396 (3.8%)	18	34/408 (8.3%)	36	1/50 (2%)	7
Pain	22/396 (5.6%)	26	26/408 (6.4%)	31	0/50 (0%)	0
Chest pain	21/396 (5.3%)	24	15/408 (3.7%)	17	0/50 (0%)	0
Influenza like illness	10/396 (2.5%)	12	23/408 (5.6%)	41	2/50 (4%)	2
Immune system disorders
Hypersensitivity	21/396 (5.3%)	29	28/408 (6.9%)	33	1/50 (2%)	1
Infections and infestations
Upper respiratory tract infection	57/396 (14.4%)	99	90/408 (22.1%)	174	13/50 (26%)	32
Nasopharyngitis	60/396 (15.2%)	108	76/408 (18.6%)	161	13/50 (26%)	58
Urinary tract infection	29/396 (7.3%)	39	39/408 (9.6%)	65	4/50 (8%)	6
Paronychia	16/396 (4%)	23	32/408 (7.8%)	45	6/50 (12%)	8
Conjunctivitis	19/396 (4.8%)	22	31/408 (7.6%)	45	2/50 (4%)	2
Influenza	22/396 (5.6%)	33	30/408 (7.4%)	43	6/50 (12%)	10
Rhinitis	22/396 (5.6%)	35	22/408 (5.4%)	50	4/50 (8%)	13
Pneumonia	8/396 (2%)	8	12/408 (2.9%)	20	4/50 (8%)	4
Cystitis	6/396 (1.5%)	7	16/408 (3.9%)	25	5/50 (10%)	6
Cellulitis	12/396 (3%)	14	16/408 (3.9%)	20	3/50 (6%)	6
Bronchitis	15/396 (3.8%)	19	16/408 (3.9%)	29	4/50 (8%)	5
Pharyngitis	9/396 (2.3%)	10	22/408 (5.4%)	28	3/50 (6%)	6
Investigations
Weight decreased	19/396 (4.8%)	22	37/408 (9.1%)	51	3/50 (6%)	3
Weight increased	22/396 (5.6%)	35	17/408 (4.2%)	21	0/50 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	106/396 (26.8%)	176	120/408 (29.4%)	229	2/50 (4%)	3
Hypokalaemia	21/396 (5.3%)	28	37/408 (9.1%)	60	3/50 (6%)	3
Hyperglycaemia	11/396 (2.8%)	24	17/408 (4.2%)	19	3/50 (6%)	4
Musculoskeletal and connective tissue disorders
Myalgia	98/396 (24.7%)	209	97/408 (23.8%)	202	5/50 (10%)	30
Arthralgia	71/396 (17.9%)	130	83/408 (20.3%)	133	5/50 (10%)	5
Pain in extremity	52/396 (13.1%)	79	76/408 (18.6%)	116	5/50 (10%)	6
Back pain	48/396 (12.1%)	58	66/408 (16.2%)	98	6/50 (12%)	17
Bone pain	31/396 (7.8%)	56	37/408 (9.1%)	48	1/50 (2%)	1
Musculoskeletal pain	38/396 (9.6%)	57	40/408 (9.8%)	51	2/50 (4%)	2
Muscle spasms	20/396 (5.1%)	24	50/408 (12.3%)	94	3/50 (6%)	5
Musculoskeletal chest pain	17/396 (4.3%)	22	22/408 (5.4%)	27	1/50 (2%)	1
Nervous system disorders
Neuropathy peripheral	79/396 (19.9%)	114	95/408 (23.3%)	138	1/50 (2%)	1
Headache	76/396 (19.2%)	128	106/408 (26%)	187	7/50 (14%)	9
Dysgeusia	62/396 (15.7%)	116	75/408 (18.4%)	95	1/50 (2%)	30
Peripheral sensory neuropathy	59/396 (14.9%)	82	52/408 (12.7%)	93	2/50 (4%)	2
Dizziness	53/396 (13.4%)	73	67/408 (16.4%)	133	4/50 (8%)	4
Paraesthesia	41/396 (10.4%)	60	43/408 (10.5%)	52	0/50 (0%)	0
Hypoaesthesia	11/396 (2.8%)	15	21/408 (5.1%)	28	1/50 (2%)	1
Psychiatric disorders
Insomnia	55/396 (13.9%)	72	67/408 (16.4%)	95	2/50 (4%)	3
Depression	20/396 (5.1%)	22	26/408 (6.4%)	33	2/50 (4%)	2
Anxiety	20/396 (5.1%)	28	20/408 (4.9%)	25	1/50 (2%)	1
Renal and urinary disorders
Dysuria	11/396 (2.8%)	12	23/408 (5.6%)	27	0/50 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	79/396 (19.9%)	118	101/408 (24.8%)	146	6/50 (12%)	10
Dyspnoea	62/396 (15.7%)	87	67/408 (16.4%)	99	1/50 (2%)	2
Epistaxis	35/396 (8.8%)	47	41/408 (10%)	56	2/50 (4%)	4
Oropharyngeal pain	27/396 (6.8%)	32	32/408 (7.8%)	55	1/50 (2%)	1
Rhinorrhoea	23/396 (5.8%)	29	33/408 (8.1%)	43	3/50 (6%)	4
Skin and subcutaneous tissue disorders
Alopecia	240/396 (60.6%)	256	248/408 (60.8%)	264	4/50 (8%)	5
Rash	96/396 (24.2%)	185	156/408 (38.2%)	288	11/50 (22%)	19
Nail disorder	92/396 (23.2%)	105	96/408 (23.5%)	106	2/50 (4%)	2
Pruritus	40/396 (10.1%)	67	75/408 (18.4%)	117	6/50 (12%)	6
Dry skin	25/396 (6.3%)	26	47/408 (11.5%)	53	4/50 (8%)	6
Palmar-plantar erythrodysaesthesia syndrome	22/396 (5.6%)	25	28/408 (6.9%)	38	1/50 (2%)	1
Erythema	20/396 (5.1%)	27	23/408 (5.6%)	28	1/50 (2%)	1
Eczema	5/396 (1.3%)	6	5/408 (1.2%)	5	3/50 (6%)	3
Vascular disorders
Hypertension	31/396 (7.8%)	93	53/408 (13%)	83	4/50 (8%)	4
Hot flush	21/396 (5.3%)	39	23/408 (5.6%)	26	0/50 (0%)	0
Lymphoedema	16/396 (4%)	18	24/408 (5.9%)	25	0/50 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.