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Clinical Trial Results:
A Multicenter, Open-Label, Single-Arm Study of Pertuzumab in Combination with Trastuzumab and a Taxane in First Line Treatment of Patients with HER2-Positive Advanced (Metastatic or Locally Recurrent) Breast Cancer

Summary
EudraCT number	2011-005334-20
Trial protocol	AT FI FR ES SI GB NL DE BE HU PT GR SE IT EE LT PL
Global end of trial date	20 Sep 2019

Results information
Results version number	v1(current)
This version publication date	16 Sep 2020
First version publication date	16 Sep 2020
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

MO28047

ISRCTN number

US NCT number

NCT01572038

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche, Ltd.

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +41 616878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

20 Sep 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

20 Sep 2019

Global end of trial reached?

Yes

Global end of trial date

20 Sep 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective for this study was to evaluate the safety and tolerability of pertuzumab in combination with trastuzumab and a taxane.

Protection of trial subjects

This study was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. All participants were required to read and sign an informed consent form.

Background therapy

Trastuzumab was administered as an intravenous infusion on Day 1 or Day 2 of the first treatment cycle as a loading dose of 8 mg/kg, followed by 6 mg/kg on Day 1 or Day 2 of each subsequent 3-weekly cycle; in line with approved local Product Information and/or recognized clinical practice guidelines. Commercial Herceptin (trastuzumab) was obtained directly by the site for intravenous use during this study. A taxane (docetaxel or paclitaxel or nab-paclitaxel) was administered in line with the respective Product Information and/or recognized clinical practice guidelines. The taxane could have been administered before or after the monoclonal antibody (pertuzumab and trastuzumab) infusions. Commercial docetaxel and/or paclitaxel and nab-paclitaxel was obtained locally by the investigational sites.

Evidence for comparator

Actual start date of recruitment

01 Jun 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Algeria: 29

Country: Number of subjects enrolled

Argentina: 5

Country: Number of subjects enrolled

Australia: 24

Country: Number of subjects enrolled

Austria: 19

Country: Number of subjects enrolled

Belgium: 23

Country: Number of subjects enrolled

Brazil: 44

Country: Number of subjects enrolled

Canada: 34

Country: Number of subjects enrolled

China: 52

Country: Number of subjects enrolled

Ecuador: 4

Country: Number of subjects enrolled

Egypt: 26

Country: Number of subjects enrolled

Estonia: 3

Country: Number of subjects enrolled

Finland: 15

Country: Number of subjects enrolled

France: 185

Country: Number of subjects enrolled

Germany: 82

Country: Number of subjects enrolled

Greece: 40

Country: Number of subjects enrolled

Hong Kong: 5

Country: Number of subjects enrolled

Hungary: 35

Country: Number of subjects enrolled

Israel: 49

Country: Number of subjects enrolled

Italy: 115

Country: Number of subjects enrolled

Lebanon: 8

Country: Number of subjects enrolled

Lithuania: 8

Country: Number of subjects enrolled

Mexico: 46

Country: Number of subjects enrolled

Morocco: 16

Country: Number of subjects enrolled

Netherlands: 20

Country: Number of subjects enrolled

Pakistan: 17

Country: Number of subjects enrolled

Peru: 11

Country: Number of subjects enrolled

Poland: 47

Country: Number of subjects enrolled

Portugal: 24

Country: Number of subjects enrolled

Saudi Arabia: 11

Country: Number of subjects enrolled

Serbia: 15

Country: Number of subjects enrolled

Slovenia: 8

Country: Number of subjects enrolled

Spain: 168

Country: Number of subjects enrolled

Sweden: 25

Country: Number of subjects enrolled

Turkey: 30

Country: Number of subjects enrolled

Ukraine: 35

Country: Number of subjects enrolled

United Arab Emirates: 5

Country: Number of subjects enrolled

United Kingdom: 142

Country: Number of subjects enrolled

Uruguay: 6

Country: Number of subjects enrolled

Venezuela, Bolivarian Republic of: 5

Worldwide total number of subjects

1436

EEA total number of subjects

959

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

1124

From 65 to 84 years

310

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 1697 patients were screened: 261 failed screening and 1436 were enrolled in the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Pertuzumab + Trastuzumab + Taxane

Arm description

Participants received pertuzumab and trastuzumab intravenously (IV) plus taxane chemotherapy once of every 3 weeks per treatment cycle until predefined study end, unacceptable toxicity, withdrawal of consent, disease progression, or death, whichever occurred first. Taxane chemotherapy was docetaxel, paclitaxel, or nab-paclitaxel, per the investigator's choice.

Arm type

Experimental

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

RO4358451

Other name

Perjeta

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pertuzumab was administered as an intravenous infusion on Day 1 or Day 2 of the first treatment cycle as a loading dose of 840 mg, followed by 420 mg on Day 1 or Day 2 of each subsequent 3 weekly cycle.

Number of subjects in period 1	Pertuzumab + Trastuzumab + Taxane
Started	1436
Received at Least One Dose of Study Drug	1436
Completed	445
Not completed	991
Enrolled into Another Trial	3
Participated in Another Trial	3
Termination by Sponsor	2
Consent withdrawn by subject	204
Physician decision	20
Patient Decision	14
Death	648
Progressive Disease	8
Site Closed Before Completing Form	6
Sponsor Decision	1
Lost to follow-up	81
Patient Deterioration	1

Baseline characteristics

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Reporting group title

Pertuzumab + Trastuzumab + Taxane

Reporting group description

Reporting group values	Pertuzumab + Trastuzumab + Taxane	Total
Number of subjects	1436	1436
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	1124	1124
From 65-84 years	310	310
85 years and over	2	2
Age Continuous
Units: Years
arithmetic mean (standard deviation)	54.4 ± 12.10	-
Sex: Female, Male
Units: Participants
Female	1429	1429
Male	7	7
Age Categorical (≤65 or >65 Years Old)
Units: Subjects
≤65 Years Old	1167	1167
>65 Years Old	269	269
Race/Ethnicity, Customized
Units: Subjects
Caucasian	1032	1032
Black	9	9
Asian	88	88
Native American	28	28
Other	57	57
Not Applicable as per Local Regulations	222	222
Ethnicity
Units: Subjects
Hispanic/Latino	269	269
Chinese	57	57
Japanese	2	2
Mixed Ethnicity	18	18
Indian	21	21
Other	495	495
Not Applicable as per Local Regulations	574	574
Geographic Region of Enrollment
Geographic region of enrollment was categorized as follows: Europe = Austria, Belgium, Estonia, Finland, France, Germany, Greece, Hungary, Italy, Lithuania, Netherlands, Poland, Portugal, Serbia, Slovenia, Spain, Sweden, United Kingdom, Ukraine; Asia = China, Hong Kong, Israel, Lebanon, Pakistan, Saudi Arabia, Turkey, United Arab Emirates; North America = Canada; South America = Argentina, Brazil, Ecuador, Mexico, Peru, Uruguay, Venezuela; Africa = Algeria, Egypt, Morocco; and Other = Australia.
Units: Subjects
Europe	1009	1009
Asia	177	177
North America	34	34
South America	121	121
Africa	71	71
Other (Australia)	24	24
Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline
Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; Grade 2: Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.
Units: Subjects
Grade 0 or 1	1371	1371
Grade 2	63	63
Missing	2	2
Visceral Disease at Baseline
The disease was considered as “visceral” if at least one lesion in a location other than breast, bone, bone marrow, lymph nodes, skin and soft tissue was observed during baseline tumor assessment. The disease was considered as “non-visceral” if all lesions observed at baseline were localized in breast, bone, bone marrow, lymph nodes, skin and soft tissue.
Units: Subjects
Visceral Disease	992	992
Non-visceral Disease	444	444
Hormone Receptor Status of Disease at Baseline
Hormone receptor status of the primary tumor and metastatic disease (combined) was defined as follows: Positive: if either estrogen receptor (ER) or progesterone receptor (PgR) status was positive; Negative: if both ER and PgR status was negative; Unknown: if both the ER and PgR status was unknown.
Units: Subjects
Positive	918	918
Negative	512	512
Unknown	6	6
Prior Neoadjuvant or Adjuvant Chemotherapy Received
Units: Subjects
Prior (Neo)Adjuvant Chemotherapy	786	786
No Prior (Neo)Adjuvant Chemotherapy	650	650
Previous Trastuzumab Therapy Received for Breast Cancer
Units: Subjects
Previous Trastuzumab Therapy	400	400
No Previous Trastuzumab Therapy	1036	1036
Initial Type of Taxane Received During the Study: Docetaxel, Paclitaxel, or Nab-Paclitaxel
Units: Subjects
Docetaxel	775	775
Paclitaxel	588	588
Nab-Paclitaxel	65	65
None	8	8
Measurable or Non-Measurable Disease (per RECIST v1.1) at Baseline
Units: Subjects
Measurable Disease	1198	1198
Non-Measurable Disease	238	238

Subject analysis set title

Europe

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Asia

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

North America

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

South America

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Africa

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Other (Australia)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Age ≤65 Years

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Age >65 Years

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Docetaxel

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received pertuzumab and trastuzumab intravenously (IV) plus taxane chemotherapy once of every 3 weeks per treatment cycle until predefined study end, unacceptable toxicity, withdrawal of consent, disease progression, or death, whichever occurred first. Participants in this subgroup received docetaxel as their taxane chemotherapy, per the investigator's choice.

Subject analysis set title

Paclitaxel

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received pertuzumab and trastuzumab intravenously (IV) plus taxane chemotherapy once of every 3 weeks per treatment cycle until predefined study end, unacceptable toxicity, withdrawal of consent, disease progression, or death, whichever occurred first. Participants in this subgroup received paclitaxel as their taxane chemotherapy, per the investigator's choice.

Subject analysis set title

Nab-Paclitaxel

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received pertuzumab and trastuzumab intravenously (IV) plus taxane chemotherapy once of every 3 weeks per treatment cycle until predefined study end, unacceptable toxicity, withdrawal of consent, disease progression, or death, whichever occurred first. Participants in this subgroup received nab-paclitaxel as their taxane chemotherapy, per the investigator's choice.

Subject analysis set title

ECOG Performance Status 0 or 1

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

ECOG Performance Status 2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Visceral Disease

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Non-Visceral Disease

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Prior (Neo)Adjuvant Chemotherapy

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

No Prior (Neo)Adjuvant Chemotherapy

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Hormone Receptor Positive

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Hormone Receptor Negative

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Hormone Receptor Status Unknown

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Previous Trastuzumab Therapy

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

No Previous Trastuzumab Therapy

Subject analysis set type

Sub-group analysis

Subject analysis set description

Europe

Asia

North America

South America

Africa

Other (Australia)

Age ≤65 Years

Age >65 Years

Docetaxel

Paclitaxel

Nab-Paclitaxel

ECOG Performance Status 0 or 1

ECOG Performance Status 2

Visceral Disease

Non-Visceral Disease

Prior (Neo)Adjuvant Chemotherapy

No Prior (Neo)Adjuvant Chemotherapy

Hormone Receptor Positive

Hormone Receptor Negative

Hormone Receptor Status Unknown

Previous Trastuzumab Therapy

No Previous Trastuzumab Therapy

Number of subjects

1009

177

121

1167

269

775

588

1371

992

444

786

650

918

512

400

1036

Units: Subjects

In utero

Preterm newborn infants (gestational age < 37 wks)

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65-84 years

85 years and over

Units: Years

arithmetic mean (standard deviation)

55.4 ± 12.14

50.8 ± 11.75

56.3 ± 11.32

54.5 ± 11.53

48.0 ± 10.55

53.8 ± 11.49

50.3 ± 9.30

72.0 ± 4.68

52.9 ± 11.77

56.3 ± 12.21

54.1 ± 12.53

54.2 ± 12.00

58.1 ± 13.81

54.6 ± 12.05

53.8 ± 12.21

54.6 ± 11.79

54.0 ± 12.46

54.1 ± 12.07

54.9 ± 12.17

46.7 ± 7.31

52.8 ± 11.80

55.0 ± 12.16

Units: Participants

Female

Male

Units: Subjects

≤65 Years Old

>65 Years Old

Units: Subjects

Caucasian

Black

Asian

Native American

Other

Not Applicable as per Local Regulations

Units: Subjects

Hispanic/Latino

Chinese

Japanese

Mixed Ethnicity

Indian

Other

Not Applicable as per Local Regulations

Geographic region of enrollment was categorized as follows: Europe = Austria, Belgium, Estonia, Finland, France, Germany, Greece, Hungary, Italy, Lithuania, Netherlands, Poland, Portugal, Serbia, Slovenia, Spain, Sweden, United Kingdom, Ukraine; Asia = China, Hong Kong, Israel, Lebanon, Pakistan, Saudi Arabia, Turkey, United Arab Emirates; North America = Canada; South America = Argentina, Brazil, Ecuador, Mexico, Peru, Uruguay, Venezuela; Africa = Algeria, Egypt, Morocco; and Other = Australia.

Units: Subjects

Europe

Asia

North America

South America

Africa

Other (Australia)

Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; Grade 2: Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.

Units: Subjects

Grade 0 or 1

Grade 2

Missing

The disease was considered as “visceral” if at least one lesion in a location other than breast, bone, bone marrow, lymph nodes, skin and soft tissue was observed during baseline tumor assessment. The disease was considered as “non-visceral” if all lesions observed at baseline were localized in breast, bone, bone marrow, lymph nodes, skin and soft tissue.

Units: Subjects

Visceral Disease

Non-visceral Disease

Hormone receptor status of the primary tumor and metastatic disease (combined) was defined as follows: Positive: if either estrogen receptor (ER) or progesterone receptor (PgR) status was positive; Negative: if both ER and PgR status was negative; Unknown: if both the ER and PgR status was unknown.

Units: Subjects

Positive

Negative

Unknown

Units: Subjects

Prior (Neo)Adjuvant Chemotherapy

No Prior (Neo)Adjuvant Chemotherapy

Units: Subjects

Previous Trastuzumab Therapy

No Previous Trastuzumab Therapy

Units: Subjects

Docetaxel

Paclitaxel

Nab-Paclitaxel

None

Units: Subjects

Measurable Disease

Non-Measurable Disease

End points

Top of page

Reporting group title

Pertuzumab + Trastuzumab + Taxane

Reporting group description

Subject analysis set title

Europe

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Asia

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

North America

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

South America

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Africa

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Other (Australia)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Age ≤65 Years

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Age >65 Years

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Docetaxel

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received pertuzumab and trastuzumab intravenously (IV) plus taxane chemotherapy once of every 3 weeks per treatment cycle until predefined study end, unacceptable toxicity, withdrawal of consent, disease progression, or death, whichever occurred first. Participants in this subgroup received docetaxel as their taxane chemotherapy, per the investigator's choice.

Subject analysis set title

Paclitaxel

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received pertuzumab and trastuzumab intravenously (IV) plus taxane chemotherapy once of every 3 weeks per treatment cycle until predefined study end, unacceptable toxicity, withdrawal of consent, disease progression, or death, whichever occurred first. Participants in this subgroup received paclitaxel as their taxane chemotherapy, per the investigator's choice.

Subject analysis set title

Nab-Paclitaxel

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received pertuzumab and trastuzumab intravenously (IV) plus taxane chemotherapy once of every 3 weeks per treatment cycle until predefined study end, unacceptable toxicity, withdrawal of consent, disease progression, or death, whichever occurred first. Participants in this subgroup received nab-paclitaxel as their taxane chemotherapy, per the investigator's choice.

Subject analysis set title

ECOG Performance Status 0 or 1

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

ECOG Performance Status 2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Visceral Disease

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Non-Visceral Disease

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Prior (Neo)Adjuvant Chemotherapy

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

No Prior (Neo)Adjuvant Chemotherapy

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Hormone Receptor Positive

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Hormone Receptor Negative

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Hormone Receptor Status Unknown

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Previous Trastuzumab Therapy

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

No Previous Trastuzumab Therapy

Subject analysis set type

Sub-group analysis

Subject analysis set description

Primary: Overview of the Number of Participants with at Least One Treatment-Emergent Adverse Event, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE v4.0)

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End point title

Overview of the Number of Participants with at Least One Treatment-Emergent Adverse Event, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE v4.0) ^[1]

End point description

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. TEAEs to monitor included anaphylaxis and hypersensitivity, cardiac dysfunction, diarrhoea Grade ≥3, pregnancy-related AEs, interstitial lung disease, infusion-/administration-related reactions, mucositis, (febrile) neutropenia, rash/skin reactions, and suspected transmission of infectious agent. TEAEs of special interest included LVEF decreased, liver enzymes increased, and suspected transmission of infectious agent by the study drug.

End point type

Primary

End point timeframe

From Baseline until 28 days after, or 7 months after (only for serious AEs related to study drug), the last dose of study treatment. The median (full range) duration of exposure to any study treatment was 16.2 (0.0-86.4) months.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Any TEAE - Any Grade	1419
Any TEAE - Grade 3 or Higher (≥3)	879
Any Serious TEAE	535
Any TEAE Leading to Death	31
Any TEAE Related to Pertuzumab - Any Grade	1037
Any TEAE Related to Trastuzumab - Any Grade	946
Any TEAE Related to Taxane - Any Grade	1342
Any TEAE Related to Pertuzumab - Grade ≥3	286
Any TEAE Related to Trastuzumab - Grade ≥3	245
Any TEAE Related to Taxane - Grade ≥3	514
Any TEAE Leading to Interruption of Pertuzumab	334
Any TEAE Leading to Interruption of Trastuzumab	386
Any TEAE Leading to Interruption of Taxane	354
Any TEAE Leading to Discontinuation of Pertuzumab	140
Any TEAE Leading to Discontinuation of Trastuzumab	133
Any TEAE Leading to Discontinuation of Taxane	286
Any TEAE to Monitor - Any Grade	1320
Any TEAE to Monitor - Grade ≥3	535
Any TEAE of Special Interest	91
Any TEAE Within 28 Days of Treatmt Discontinuation	975

No statistical analyses for this end point

Primary: Number of Participants Who Died Over the Course of the Study by Reported Cause of Death (Adverse Events Leading to Death by System Organ Class and Preferred Term)

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End point title

Number of Participants Who Died Over the Course of the Study by Reported Cause of Death (Adverse Events Leading to Death by System Organ Class and Preferred Term) ^[2]

End point description

All adverse events leading to death, regardless of whether they were classified as treatment emergent, are listed by system organ class (SOC) and preferred term (PT) according to the Medical Dictionary for Regulatory Activities, version 22.1 (MedDRA version 22.1); PTs that are part of a given SOC are listed in the rows directly below each SOC within the results table. Admin. = administration; Mediast. = mediastinal

End point type

Primary

End point timeframe

The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Total Number of Deaths	658
Number of Deaths by Cause: Progressive Disease	581
Number of Deaths by Cause: Other	42
Number of Deaths by Cause: Adverse Event (Total)	35
Infections and Infestations (SOC)	11
Peritonitis (PT)	1
Pneumonia (PT)	5
Respiratory Tract Infection (PT)	1
Sepsis (PT)	3
Septic Shock (PT)	1
Cardiac Disorders (SOC)	7
Cardiac Arrest (PT)	2
Cardiac Failure (PT)	1
Cardiac Failure Congestive (PT)	1
Cardio-respiratory Arrest (PT)	1
Myocardial Infarction (PT)	1
Right Ventricular Failure (PT)	1
General Disorders & Admin. Site Conditions (SOC)	6
Death (PT)	6
Blood and Lymphatic System Disorders (SOC)	3
Febrile Neutropenia (PT)	1
Neutropenia (PT)	1
Thrombocytopenia (PT)	1
Respiratory, Thoracic & Mediast. Disorders (SOC)	3
Acute Respiratory Distress Syndrome (PT)	1
Aspiration (PT)	1
Pneumonitis (PT)	1
Gastrointestinal Disorders (SOC)	2
Pancreatitis (PT)	1
Pancreatitis Chronic (PT)	1
Nervous System Disorders (SOC)	2
Hepatic Encephalopathy (PT)	1
Ischemic Stroke (PT)	1
Metabolism and Nutrition Disorders (SOC)	1
Hypoglycaemia (PT)	1
Hepatobiliary Disorders (SOC)	1
Hepatic Failure (PT)	1
Psychiatric Disorders (SOC)	1
Delirium (PT)	1

No statistical analyses for this end point

Primary: Number of Participants Who Died Within 6 Months of Starting Study Treatment by Reported Cause of Death (Adverse Events Leading to Death by System Organ Class and Preferred Term)

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End point title

Number of Participants Who Died Within 6 Months of Starting Study Treatment by Reported Cause of Death (Adverse Events Leading to Death by System Organ Class and Preferred Term) ^[3]

End point description

End point type

Primary

End point timeframe

The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Total Number of Deaths	38
Number of Deaths by Cause: Progressive Disease	18
Number of Deaths by Cause: Other	1
Number of Deaths by Cause: Adverse Event (Total)	19
Infections and Infestations (SOC)	6
Peritonitis (PT)	1
Pneumonia (PT)	2
Respiratory Tract Infection (PT)	1
Sepsis (PT)	2
General Disorders & Admin. Site Conditions (SOC)	4
Death (PT)	4
Blood and Lymphatic System Disorders (SOC)	3
Febrile Neutropenia (PT)	1
Neutropenia (PT)	1
Thrombocytopenia (PT)	1
Cardiac Disorders (SOC)	2
Cardiac Arrest (PT)	1
Cardio-Respiratory Arrest (PT)	1
Respiratory, Thoracic & Mediast. Disorders (SOC)	2
Acute Respiratory Distress Syndrome (PT)	1
Pneumonitis (PT)	1
Gastrointestinal Disorders (SOC)	1
Pancreatitis (PT)	1
Nervous System Disorders (SOC)	1
Hepatic Encephalopathy (PT)	1
Metabolism and Nutrition Disorders (SOC)	1
Hypoglycaemia (PT)	1
Hepatobiliary Disorders (SOC)	1
Hepatic Failure (PT)	1

No statistical analyses for this end point

Primary: Number of Participants with Grade ≥3 Treatment-Emergent Adverse Events, Occurring in ≥1% of Participants by System Organ Class and Preferred Term

Top of page

End point title

Number of Participants with Grade ≥3 Treatment-Emergent Adverse Events, Occurring in ≥1% of Participants by System Organ Class and Preferred Term ^[4]

End point description

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. MedDRA version 22.1 was used to code AEs by system organ class (SOC) and preferred term (PT); PTs that are part of a given SOC are listed in the rows directly below each SOC within the results table. If a participant experienced the same AE at more than one severity grade, only the most severe grade was presented.

End point type

Primary

End point timeframe

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Any TEAE - Grade (Gr.) 3	676
Any TEAE - Gr. 4	172
Any TEAE - Gr. 5	31
Gastrointestinal Disorders (SOC) - Gr. 3	163
Gastrointestinal Disorders (SOC) - Gr. 4	4
Gastrointestinal Disorders (SOC) - Gr. 5	2
Diarrhoea (PT) - Gr. 3	119
Diarrhoea (PT) - Gr. 4	1
Diarrhoea (PT) - Gr. 5	0
Vomiting (PT) - Gr. 3	19
Vomiting (PT) - Gr. 4	0
Vomiting (PT) - Gr. 5	0
Skin & Subcutaneous Tissue Disorders (SOC) - Gr. 3	56
Skin & Subcutaneous Tissue Disorders (SOC) - Gr. 4	0
Skin & Subcutaneous Tissue Disorders (SOC) - Gr. 5	0
Gen. Disorders & Admin.Site Conditions (SOC)-Gr. 3	100
Gen. Disorders & Admin.Site Conditions (SOC)-Gr. 4	0
Gen. Disorders & Admin.Site Conditions (SOC)-Gr. 5	3
Fatigue (PT) - Gr. 3	36
Fatigue (PT) - Gr. 4	0
Fatigue (PT) - Gr. 5	0
Asthenia (PT) - Gr. 3	29
Asthenia (PT) - Gr. 4	0
Asthenia (PT) - Gr. 5	0
Mucosal Inflammation (PT) - Gr. 3	14
Mucosal Inflammation (PT) - Gr. 4	0
Mucosal Inflammation (PT) - Gr. 5	0
Nervous System Disorders (SOC) - Gr. 3	139
Nervous System Disorders (SOC) - Gr. 4	0
Nervous System Disorders (SOC) - Gr. 5	2
Neuropathy Peripheral (PT) - Gr. 3	26
Neuropathy Peripheral (PT) - Gr. 4	0
Neuropathy Peripheral (PT) - Gr. 5	0
Syncope (PT) - Gr. 3	24
Syncope (PT) - Gr. 4	0
Syncope (PT) - Gr. 5	0
Headache (PT) - Gr. 3	17
Headache (PT) - Gr. 4	0
Headache (PT) - Gr. 5	0
Paraesthesia (PT) - Gr. 3	14
Paraesthesia (PT) - Gr. 4	0
Paraesthesia (PT) - Gr. 5	0
Peripheral Sensory Neuropathy (PT) - Gr. 3	14
Peripheral Sensory Neuropathy (PT) - Gr. 4	0
Peripheral Sensory Neuropathy (PT) - Gr. 5	0
Infections and Infestations (SOC) - Gr. 3	148
Infections and Infestations (SOC) - Gr. 4	19
Infections and Infestations (SOC) - Gr. 5	10
Pneumonia (PT) - Gr. 3	22
Pneumonia (PT) - Gr. 4	1
Pneumonia (PT) - Gr. 5	4
Vascular Device Infection (PT) - Gr. 3	14
Vascular Device Infection (PT) - Gr. 4	0
Vascular Device Infection (PT) - Gr. 5	0
Device Related Infection (PT) - Gr. 3	14
Device Related Infection (PT) - Gr. 4	0
Device Related Infection (PT) - Gr. 5	0
Musculo. & Connective Tissue Disorders (SOC)-Gr. 3	75
Musculo. & Connective Tissue Disorders (SOC)-Gr. 4	0
Musculo. & Connective Tissue Disorders (SOC)-Gr. 5	0
Resp., Thoracic & Mediast. Disorders (SOC) - Gr. 3	62
Resp., Thoracic & Mediast. Disorders (SOC) - Gr. 4	5
Resp., Thoracic & Mediast. Disorders (SOC) - Gr. 5	3
Pulmonary Embolism (PT) - Gr. 3	21
Pulmonary Embolism (PT) - Gr. 4	2
Pulmonary Embolism (PT) - Gr. 5	0
Dyspnoea (PT) - Gr. 3	19
Dyspnoea (PT) - Gr. 4	1
Dyspnoea (PT) - Gr. 5	0
Blood & Lymphatic System Disorders (SOC) - Gr. 3	158
Blood & Lymphatic System Disorders (SOC) - Gr. 4	104
Blood & Lymphatic System Disorders (SOC) - Gr. 5	3
Neutropenia (PT) - Gr. 3	77
Neutropenia (PT) - Gr. 4	67
Neutropenia (PT) - Gr. 5	1
Febrile Neutropenia (PT) - Gr. 3	51
Febrile Neutropenia (PT) - Gr. 4	38
Febrile Neutropenia (PT) - Gr. 5	1
Anaemia (PT) - Gr. 3	29
Anaemia (PT) - Gr. 4	0
Anaemia (PT) - Gr. 5	0
Leukopenia (PT) - Gr. 3	15
Leukopenia (PT) - Gr. 4	3
Leukopenia (PT) - Gr. 5	0
Investigations (SOC) - Gr. 3	116
Investigations (SOC) - Gr. 4	20
Investigations (SOC) - Gr. 5	0
Neutrophil Count Decreased (PT) - Gr. 3	25
Neutrophil Count Decreased (PT) - Gr. 4	13
Neutrophil Count Decreased (PT) - Gr. 5	0
Ejection Fraction Decreased (PT) - Gr. 3	22
Ejection Fraction Decreased (PT) - Gr. 4	2
Ejection Fraction Decreased (PT) - Gr. 5	0
Gamma-Glutamyltransferase Increased (PT) - Gr. 3	19
Gamma-Glutamyltransferase Increased (PT) - Gr. 4	1
Gamma-Glutamyltransferase Increased (PT) - Gr. 5	0
White Blood Cell Count Decreased (PT) - Gr. 3	16
White Blood Cell Count Decreased (PT) - Gr. 4	2
White Blood Cell Count Decreased (PT) - Gr. 5	0
Alanine Aminotransferase Increased (PT) - Gr. 3	16
Alanine Aminotransferase Increased (PT) - Gr. 4	0
Alanine Aminotransferase Increased (PT) - Gr. 5	0
Metabolism and Nutrition Disorders (SOC) - Gr. 3	63
Metabolism and Nutrition Disorders (SOC) - Gr. 4	8
Metabolism and Nutrition Disorders (SOC) - Gr. 5	1
Hypokalaemia (PT) - Gr. 3	19
Hypokalaemia (PT) - Gr. 4	1
Hypokalaemia (PT) - Gr. 5	0
Vascular Disorders (SOC) - Gr. 3	62
Vascular Disorders (SOC) - Gr. 4	2
Vascular Disorders (SOC) - Gr. 5	0
Hypertension (PT) - Gr. 3	45
Hypertension (PT) - Gr. 4	1
Hypertension (PT) - Gr. 5	0
Psychiatric Disorders (SOC) - Gr. 3	15
Psychiatric Disorders (SOC) - Gr. 4	3
Psychiatric Disorders (SOC) - Gr. 5	1
Injury, Poisoning & Proced. Complicat. (SOC)-Gr. 3	43
Injury, Poisoning & Proced. Complicat. (SOC)-Gr. 4	6
Injury, Poisoning & Proced. Complicat. (SOC)-Gr. 5	0
Cardiac Disorders (SOC) - Gr. 3	35
Cardiac Disorders (SOC) - Gr. 4	5
Cardiac Disorders (SOC) - Gr. 5	7
Immune System Disorders (SOC) - Gr. 3	17
Immune System Disorders (SOC) - Gr. 4	1
Immune System Disorders (SOC) - Gr. 5	0
Renal and Urinary Disorders (SOC) - Gr. 3	15
Renal and Urinary Disorders (SOC) - Gr. 4	3
Renal and Urinary Disorders (SOC) - Gr. 5	0
Neoplasms Benign, Malignant & Unspec. (SOC) -Gr. 3	13
Neoplasms Benign, Malignant & Unspec. (SOC) -Gr. 4	5
Neoplasms Benign, Malignant & Unspec. (SOC) -Gr. 5	0
Hepatobiliary Disorders (SOC) - Gr. 3	13
Hepatobiliary Disorders (SOC) - Gr. 4	0
Hepatobiliary Disorders (SOC) - Gr. 5	1

No statistical analyses for this end point

Primary: Number of Participants with Treatment-Emergent Adverse Events of Any Grade That Were Related to Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥10% of Participants by System Organ Class

Top of page

End point title

Number of Participants with Treatment-Emergent Adverse Events of Any Grade That Were Related to Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥10% of Participants by System Organ Class ^[5]

End point description

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. MedDRA version 22.1 was used to code AEs and the system organ classes are presented in descending order according to the total frequency of occurrence. If a participant experienced more than one event in a category, they were counted only once in that category.

End point type

Primary

End point timeframe

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Any TEAE Related to Pertuzumab (Rel to Ptz)	1037
Rel to Ptz: Gastrointestinal Disorders	629
Rel to Ptz: Skin and Subcutaneous Tissue Disorders	491
Rel to Ptz: Gen. Disorders & Admin.Site Conditions	462
Rel to Ptz: Investigations	252
Rel to Ptz: Nervous System Disorders	207
Rel to Ptz: Resp., Thoracic & Mediast. Disorders	188
Rel to Ptz: Musculo. & Connective Tissue Disorders	184
Rel to Ptz: Blood & Lymphatic System Disorders	182
Rel to Ptz: Infections and Infestations	151
Any TEAE Related to Trastuzumab (Rel to Trz)	946
Rel to Trz: Gastrointestinal Disorders	435
Rel to Trz: Gen. Disorders & Admin.Site Conditions	434
Rel to Trz: Skin and Subcutaneous Tissue Disorders	384
Rel to Trz: Investigations	262
Rel to Trz: Nervous System Disorders	184
Rel to Trz: Musculo. & Connective Tissue Disorders	179
Rel to Trz: Blood & Lymphatic System Disorders	163
Rel to Trz: Resp., Thoracic & Mediast. Disorders	153
Any TEAE Related to Taxane (Rel to Tax)	1342
Rel to Tax: Gastrointestinal Disorders	984
Rel to Tax: Skin and Subcutaneous Tissue Disorders	938
Rel to Tax: Gen. Disorders & Admin.Site Conditions	834
Rel to Tax: Nervous System Disorders	764
Rel to Tax: Blood & Lymphatic System Disorders	457
Rel to Tax: Musculo. & Connective Tissue Disorders	386
Rel to Tax: Infections and Infestations	293
Rel to Tax: Resp., Thoracic & Mediast. Disorders	290
Rel to Tax: Metabolism and Nutrition Disorders	227
Rel to Tax: Investigations	201
Rel to Tax: Eye Disorders	174

No statistical analyses for this end point

Primary: Number of Participants with Grade ≥3 Treatment-Emergent Adverse Events That Were Related to Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥0.5% of Participants by Preferred Term

Top of page

End point title

Number of Participants with Grade ≥3 Treatment-Emergent Adverse Events That Were Related to Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥0.5% of Participants by Preferred Term ^[6]

End point description

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. MedDRA version 22.1 was used to code AEs and the preferred terms are presented in descending order according to the total frequency of occurrence. If a participant experienced more than one event in a category, they were counted only once in that category.

End point type

Primary

End point timeframe

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Any Grade ≥3 TEAE Related to Pertuz. (Rel to Ptz)	286
Rel to Ptz: Diarrhoea	59
Rel to Ptz: Neutropenia	28
Rel to Ptz: Febrile Neutropenia	28
Rel to Ptz: Ejection Fraction Decreased	19
Rel to Ptz: Neutrophil Count Decreased	15
Rel to Ptz: Fatigue	15
Rel to Ptz: Left Ventricular Dysfunction	10
Rel to Ptz: Asthenia	10
Rel to Ptz: White Blood Cell Count Decreased	10
Rel to Ptz: Cardiac Failure	9
Any Grade ≥3 TEAE Related to Trastuz. (Rel to Trz)	245
Rel to Trz: Diarrhoea	32
Rel to Trz: Neutropenia	30
Rel to Trz: Ejection Fraction Decreased	23
Rel to Trz: Febrile Neutropenia	21
Rel to Trz: Neutrophil Count Decreased	15
Rel to Trz: Fatigue	14
Rel to Trz: Left Ventricular Dysfunction	11
Rel to Trz: White Blood Cell Count Decreased	10
Rel to Trz: Cardiac Failure	8
Rel to Trz: Asthenia	8
Any Grade ≥3 TEAE Related to Taxane (Rel to Tax)	514
Rel to Tax: Neutropenia	140
Rel to Tax: Febrile Neutropenia	86
Rel to Tax: Diarrhoea	80
Rel to Tax: Neutrophil Count Decreased	34
Rel to Tax: Fatigue	26
Rel to Tax: Peripheral Neuropathy	24
Rel to Tax: Asthenia	20
Rel to Tax: Leukopenia	16
Rel to Tax: White Blood Cell Count Decreased	16
Rel to Tax: Mucosal Inflammation	14
Rel to Tax: Paraesthesia	13
Rel to Tax: Peripheral Sensory Neuropathy	13
Rel to Tax: Onycholysis	10
Rel to Tax: Neutropenic Sepsis	10
Rel to Tax: Anaemia	10
Rel to Tax: Vomiting	7
Rel to Tax: Neurotoxicity	7

No statistical analyses for this end point

Primary: Number of Participants with Treatment-Emergent Adverse Events Leading to Discontinuation of Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥0.2% of Participants by Preferred Term

Top of page

End point title

Number of Participants with Treatment-Emergent Adverse Events Leading to Discontinuation of Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥0.2% of Participants by Preferred Term ^[7]

End point description

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. MedDRA version 22.1 was used to code AEs and the preferred terms are presented in descending order according to the total frequency of occurrence. If a participant experienced more than one event in a category, they were counted only once in that category. Discont. = discontinuation; Ptz = pertuzumab; Tax = taxane; Trz = trastuzumab

End point type

Primary

End point timeframe

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Any TEAE, Pertuzumab Discontinuation (Ptz Discont)	140
Ptz Discont: Ejection Fraction Decreased	37
Ptz Discont: Cardiac Failure	10
Ptz Discont: Left Ventricular Dysfunction	7
Ptz Discont: Diarrhoea	7
Ptz Discont: Dyspnoea	4
Ptz Discont: Infusion Related Reaction	4
Ptz Discont: Sepsis	3
Ptz Discont: Neuropathy Peripheral	3
Ptz Discont: Hypersensitivity	3
Ptz Discont: General Physical Health Deterioration	3
Any TEAE, Trastuzumab Discontinuation(Trz Discont)	133
Trz Discont: Ejection Fraction Decreased	37
Trz Discont: Cardiac Failure	10
Trz Discont: Left Ventricular Dysfunction	7
Trz Discont: Diarrhoea	6
Trz Discont: Sepsis	3
Trz Discont: Dyspnoea	3
Trz Discont: Neuropathy Peripheral	3
Trz Discont: Hypersensitivity	3
Trz Discont: General Physical Health Deterioration	3
Any TEAE, Taxane Discontinuation (Tax Discont)	286
Tax Discont: Neuropathy Peripheral	52
Tax Discont: Peripheral Sensory Neuropathy	25
Tax Discont: Paraesthesia	24
Tax Discont: Diarrhoea	19
Tax Discont: Fatigue	16
Tax Discont: Asthenia	13
Tax Discont: Onycholysis	8
Tax Discont: Nail Toxicity	7
Tax Discont: Neurotoxicity	7
Tax Discont: Polyneuropathy	7
Tax Discont: Oedema Peripheral	7
Tax Discont: Febrile Neutropenia	7
Tax Discont: Neutropenia	7
Tax Discont: Dyspnoea	6
Tax Discont: Decreased Appetite	6
Tax Discont: Ejection Fraction Decreased	5
Tax Discont: General Physical Health Deterioration	4
Tax Discont: Mucosal Inflammation	4
Tax Discont: Rash	4
Tax Discont: Anaemia	4
Tax Discont: Arthralgia	4
Tax Discont: Drug Hypersensitivity	4
Tax Discont: Dysgeusia	3
Tax Discont: Nail Disorder	3
Tax Discont: Nail Dystrophy	3
Tax Discont: Skin Toxicity	3
Tax Discont: Pneumonia	3
Tax Discont: Sepsis	3
Tax Discont: Pleural Effusion	3
Tax Discont: Pneumonitis	3
Tax Discont: Cardiac Failure	3
Tax Discont: Myalgia	3

No statistical analyses for this end point

Primary: Number of Participants with Treatment-Emergent Adverse Events Leading to Dose Interruption of Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥0.5% of Participants by Preferred Term

Top of page

End point title

Number of Participants with Treatment-Emergent Adverse Events Leading to Dose Interruption of Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥0.5% of Participants by Preferred Term ^[8]

End point description

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. MedDRA version 22.1 was used to code AEs and the preferred terms are presented in descending order according to the total frequency of occurrence. If a participant experienced more than one event in a category, they were counted only once in that category. Interrupt. = interruption; Ptz = pertuzumab; Tax = taxane; Trz = trastuzumab

End point type

Primary

End point timeframe

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Any TEAE, Pertuzumab Interruption (Ptz Interrupt)	334
Ptz Interrupt: Ejection Fraction Decreased	51
Ptz Interrupt: Diarrhoea	21
Ptz Interrupt: Neutropenia	17
Ptz Interrupt: Pneumonia	14
Ptz Interrupt: Upper Respiratory Tract Infection	13
Ptz Interrupt: Pyrexia	11
Ptz Interrupt: Dyspnoea	11
Ptz Interrupt: Drug Hypersensitivity	9
Ptz Interrupt: Influenza	8
Ptz Interrupt: Asthenia	8
Ptz Interrupt: Neutrophil Count Decreased	8
Ptz Interrupt: Nasopharyngitis	7
Ptz Interrupt: Anaemia	7
Any TEAE, Trastuzumab Interruption (Trz Interrupt)	386
Trz Interrupt: Ejection Fraction Decreased	52
Trz Interrupt: Drug Hypersensitivity	31
Trz Interrupt: Diarrhoea	20
Trz Interrupt: Pyrexia	18
Trz Interrupt: Neutropenia	17
Trz Interrupt: Dyspnoea	17
Trz Interrupt: Pneumonia	14
Trz Interrupt: Chills	13
Trz Interrupt: Infusion Related Reaction	13
Trz Interrupt: Upper Respiratory Tract Infection	12
Trz Interrupt: Neutrophil Count Decreased	8
Trz Interrupt: Influenza	7
Trz Interrupt: Asthenia	7
Trz Interrupt: Vomiting	7
Trz Interrupt: Anaemia	7
Trz Interrupt: Nasopharyngitis	7
Any TEAE, Taxane Interruption (Tax Interrupt)	354
Tax Interrupt: Neutropenia	46
Tax Interrupt: Diarrhoea	30
Tax Interrupt: Leukopenia	17
Tax Interrupt: Dyspnoea	15
Tax Interrupt: Pyrexia	14
Tax Interrupt: Neutrophil Count Decreased	14
Tax Interrupt: Ejection Fraction Decreased	13
Tax Interrupt: Neuropathy Peripheral	13
Tax Interrupt: Nasopharyngitis	10
Tax Interrupt: Drug Hypersensitivity	10
Tax Interrupt: Fatigue	10
Tax Interrupt: Upper Respiratory Tract Infection	9
Tax Interrupt: Infusion Related Reaction	9
Tax Interrupt: Asthenia	9
Tax Interrupt: Erythema	8
Tax Interrupt: Pneumonia	7
Tax Interrupt: Flushing	7
Tax Interrupt: Hypersensitivity	7

No statistical analyses for this end point

Primary: Number of Participants with Treatment-Emergent Adverse Events to Monitor of Any Grade, Occurring in ≥5% of Participants by Category

Top of page

End point title

Number of Participants with Treatment-Emergent Adverse Events to Monitor of Any Grade, Occurring in ≥5% of Participants by Category ^[9]

End point description

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first dose of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, it was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. If a participant had more than one event in a category, they were counted only once in that category. TEAEs to monitor included anaphylaxis and hypersensitivity, cardiac dysfunction, diarrhoea Grade ≥3, pregnancy-related AEs, interstitial lung disease, infusion-/administration-related reactions, mucositis, (febrile) neutropenia, rash/skin reactions, and suspected transmission of infectious agent. MedDRA version 22.1 was used to code AEs; AEs may fall within multiple categories.

End point type

Primary

End point timeframe

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Any TEAE to Monitor	1320
Infusion-/Administration-Related Reactions	1096
Rash/Skin Reactions	668
Mucositis	618
Cardiac Dysfunction	478
Neutropenia/Febrile Neutropenia	439
Anaphylaxis and Hypersensitivity	124
Diarrhoea Grade ≥3	120

No statistical analyses for this end point

Primary: Number of Participants with Grade ≥3 Treatment-Emergent Adverse Events to Monitor, Occurring in ≥0.5% of Participants by Category and Preferred Term

Top of page

End point title

Number of Participants with Grade ≥3 Treatment-Emergent Adverse Events to Monitor, Occurring in ≥0.5% of Participants by Category and Preferred Term ^[10]

End point description

End point type

Primary

End point timeframe

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Any Grade ≥3 TEAE to Monitor	535
Neutropenia/Febrile Neutropenia (Category)	279
Neutropenia (PT)	145
Febrile Neutropenia (PT)	90
Neutrophil Count Decreased (PT)	38
Leukopenia (PT)	18
White Blood Cell Count Decreased (PT)	18
Neutropenic Sepsis (PT)	10
Infusion-/Admin.-Related Reactions (Category)	123
Hypertension (PT)	27
IRR/ARR: Drug Hypersensitivity (PT)	12
Asthenia (PT)	11
Fatigue (PT)	11
Dyspnoea (PT)	10
Infusion Related Reaction (PT)	8
Paraesthesia (PT)	7
Diarrhoea Grade ≥3 (Category)	120
Diarrhoea (PT)	120
Cardiac Dysfunction (Category)	51
Ejection Fraction Decreased (PT)	24
Left Ventricular Dysfunction (PT)	11
Cardiac Failure (PT)	9
Mucositis (Category)	33
Mucosal Inflammation (PT)	14
Stomatitis (PT)	9
Rash/Skin Reactions (Category)	28
Rash (PT)	10
Anaphylaxis and Hypersensitivity (Category)	18
Anaphyl./Hypersens.: Drug Hypersensitivity (PT)	13

No statistical analyses for this end point

Primary: Number of Participants with Treatment-Emergent Adverse Events of Special Interest by Category and Preferred Term

Top of page

End point title

Number of Participants with Treatment-Emergent Adverse Events of Special Interest by Category and Preferred Term ^[11]

End point description

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. TEAEs of special interest included LVEF decreased, liver enzymes (ALT or AST) increased, and suspected transmission of infectious agent by the study drug. MedDRA version 22.1 was used to code AEs; preferred terms (PT) that are part of a given category are listed in the rows directly below each category within the results table. If a participant experienced more than one event in a category, they were counted only once in that category.

End point type

Primary

End point timeframe

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Any TEAE of Special Interest	91
Decline in LVEF (Category)	90
Ejection Fraction Decreased (PT)	75
Left Ventricular Dysfunction (PT)	8
Cardiac Failure (PT)	7
Cardiac Failure Congestive (PT)	1
Elevated ALT or AST (Category)	1
Hepatic Failure (PT)	1

No statistical analyses for this end point

Primary: Subgroup Analysis by Region of Enrollment: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

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End point title

Subgroup Analysis by Region of Enrollment: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab ^[12]

End point description

End point type

Primary

End point timeframe

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Europe	Asia	North America	South America	Africa	Other (Australia)
Number of subjects analysed	1009	177	34	121	71	24
Units: Percentage of participants
number (not applicable)
Any Serious TEAE	38.16	41.81	26.47	30.58	22.54	58.33
Any TEAE - Grade 3 or Higher (≥3)	62.64	61.58	64.71	52.07	52.11	66.67
Any Grade ≥3 TEAE Related to Pertuzumab	18.53	24.86	14.71	22.31	26.76	16.67

No statistical analyses for this end point

Primary: Subgroup Analysis by Age (≤65 vs. >65 Years): Overview of Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), TEAEs Leading to Death, Grade ≥3 TEAEs, Any-Grade and Grade ≥3 TEAEs Related to Pertuzumab, and TEAEs to Monitor

Top of page

End point title

Subgroup Analysis by Age (≤65 vs. >65 Years): Overview of Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), TEAEs Leading to Death, Grade ≥3 TEAEs, Any-Grade and Grade ≥3 TEAEs Related to Pertuzumab, and TEAEs to Monitor ^[13]

End point description

End point type

Primary

End point timeframe

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Age ≤65 Years	Age >65 Years
Number of subjects analysed	1167	269
Units: Percentage of participants
number (not applicable)
Any Serious TEAE	35.56	44.61
Any TEAE Leading to Death	1.46	5.20
Any TEAE - Grade 3 or Higher (≥3)	58.95	71.00
Any TEAE Related to Pertuzumab - Any Grade	72.41	71.38
Any Grade ≥3 TEAE Related to Pertuzumab	19.19	23.05
Any TEAE to Monitor - Any Grade	92.63	88.85

No statistical analyses for this end point

Primary: Subgroup Analysis by Taxane Chemotherapy: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), TEAEs Leading to Death, Grade ≥3 TEAEs, Any-Grade and Grade ≥3 TEAEs Related to Pertuzumab, and TEAEs to Monitor

Top of page

End point title

Subgroup Analysis by Taxane Chemotherapy: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), TEAEs Leading to Death, Grade ≥3 TEAEs, Any-Grade and Grade ≥3 TEAEs Related to Pertuzumab, and TEAEs to Monitor ^[14]

End point description

End point type

Primary

End point timeframe

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Docetaxel	Paclitaxel	Nab-Paclitaxel
Number of subjects analysed	775	588	65
Units: Percentage of participants
number (not applicable)
Any Serious TEAE	38.71	35.71	33.85
Any TEAE Leading to Death	1.81	2.72	1.54
Any TEAE - Grade 3 or Higher (≥3)	63.35	59.35	55.38
Any TEAE Related to Pertuzumab - Any Grade	70.58	73.81	80.00
Any Grade ≥3 TEAE Related to Pertuzumab	22.06	17.86	13.85
Any TEAE to Monitor - Any Grade	91.48	92.01	98.46

No statistical analyses for this end point

Primary: Subgroup Analysis by ECOG Performance Status at Baseline: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

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End point title

Subgroup Analysis by ECOG Performance Status at Baseline: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab ^[15]

End point description

End point type

Primary

End point timeframe

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	ECOG Performance Status 0 or 1	ECOG Performance Status 2
Number of subjects analysed	1371	63
Units: Percentage of participants
number (not applicable)
Any Serious TEAE	36.62	52.38
Any TEAE - Grade 3 or Higher (≥3)	61.05	65.08
Any Grade ≥3 TEAE Related to Pertuzumab	19.91	20.63

No statistical analyses for this end point

Primary: Subgroup Analysis by Visceral Disease at Baseline: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

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End point title

Subgroup Analysis by Visceral Disease at Baseline: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab ^[16]

End point description

End point type

Primary

End point timeframe

Notes
[16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Visceral Disease	Non-Visceral Disease
Number of subjects analysed	992	444
Units: Percentage of participants
number (not applicable)
Any Serious TEAE	35.58	40.99
Any TEAE - Grade 3 or Higher (≥3)	61.49	60.59
Any Grade ≥3 TEAE Related to Pertuzumab	19.86	20.05

No statistical analyses for this end point

Primary: Subgroup Analysis by Prior (Neo)Adjuvant Chemotherapy: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

Top of page

End point title

Subgroup Analysis by Prior (Neo)Adjuvant Chemotherapy: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab ^[17]

End point description

End point type

Primary

End point timeframe

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Prior (Neo)Adjuvant Chemotherapy	No Prior (Neo)Adjuvant Chemotherapy
Number of subjects analysed	786	650
Units: Percentage of participants
number (not applicable)
Any Serious TEAE	36.01	38.77
Any TEAE - Grade 3 or Higher (≥3)	62.72	59.38
Any Grade ≥3 TEAE Related to Pertuzumab	21.5	18.00

No statistical analyses for this end point

Primary: Subgroup Analysis by Hormone Receptor Status at Baseline: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

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End point title

Subgroup Analysis by Hormone Receptor Status at Baseline: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab ^[18]

End point description

End point type

Primary

End point timeframe

Notes
[18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Hormone Receptor Positive	Hormone Receptor Negative	Hormone Receptor Status Unknown
Number of subjects analysed	918	512	6
Units: Percentage of participants
number (not applicable)
Any Serious TEAE	38.45	34.96	50.00
Any TEAE - Grade 3 or Higher (≥3)	62.42	59.18	50.00
Any Grade ≥3 TEAE Related to Pertuzumab	19.72	20.12	33.33

No statistical analyses for this end point

Primary: Subgroup Analysis by Previous Trastuzumab Therapy: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

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End point title

Subgroup Analysis by Previous Trastuzumab Therapy: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab ^[19]

End point description

End point type

Primary

End point timeframe

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Previous Trastuzumab Therapy	No Previous Trastuzumab Therapy
Number of subjects analysed	400	1036
Units: Percentage of participants
number (not applicable)
Any Serious TEAE	33.75	38.61
Any TEAE - Grade 3 or Higher (≥3)	59.50	61.87
Any Grade ≥3 TEAE Related to Pertuzumab	19.25	20.17

No statistical analyses for this end point

Primary: Number of Participants with a Congestive Heart Failure Event

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End point title

Number of Participants with a Congestive Heart Failure Event ^[20]

End point description

Congestive heart failure was defined as the Standardised MedDRA Query (SMQ) 'Cardiac failure (wide)' from the Medical Dictionary for Regulatory Activities, version 22.1 (MedDRA version 22.1).

End point type

Primary

End point timeframe

From Baseline until 28 days after the last dose of study treatment. The median (full range) duration of exposure to any study treatment was 16.2 (0.0-86.4) months.

Notes
[20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants	478

No statistical analyses for this end point

Primary: Time to Onset of the First Episode of Congestive Heart Failure

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End point title

Time to Onset of the First Episode of Congestive Heart Failure ^[21]

End point description

Congestive heart failure was defined as SMQ 'Cardiac failure (wide)' from the MedDRA version 22.1. Time to onset of the first episode of congestive heart failure was analyzed using a Kaplan-Meier approach. Participants who did not experience any congestive heart failure at the time of data-cut were censored at the date of the last attended visit whilst on-treatment (including visits up to and including 28 days after last dose of study treatment). Only treatment emergent congestive heart failure events are included.

End point type

Primary

End point timeframe

From Baseline until 28 days after the last dose of study treatment. The median (full range) duration of exposure to any study treatment was 16.2 (0.0-86.4) months.

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436 ^[22]
Units: Months
median (confidence interval 95%)	999999 (73.82 to 999999)

Notes
[22] - '999999' means the median and 95% CI could not be calculated because not enough events had occurred.

No statistical analyses for this end point

Primary: Change from Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study

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End point title

Change from Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study ^[23]

End point description

All participants must have had a baseline LVEF ≥50% to enroll in the study; patients with significant cardiac disease or baseline LVEF below 50% were not eligible for this study. The change from baseline LVEF values were reported at every 3 cycles over the course of the study and at the final treatment, worst treatment, and maximum decrease values. The final treatment value was defined as the last LVEF value observed before all study treatment discontinuation. The worst treatment value was defined as the lowest LVEF value observed before all study treatment discontinuation. The maximum decrease value was defined as the largest decrease of LVEF value from baseline, or minimum increase if a participant's post-baseline LVEF measures were all larger than the baseline value.

End point type

Primary

End point timeframe

Baseline, predose on Day 1 of every 3 cycles (1 cycle is 3 weeks) during treatment period, and 28 days post-treatment safety follow-up. The median (full range) duration of exposure to any study treatment was 16.2 (0.0-86.4) months.

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436 ^[24]
Units: Percentage points of LVEF
arithmetic mean (standard deviation)
Baseline (BL): Absolute Value at Visit (n = 1435)	64.6 ± 6.46
Change from BL at Cycle 3 (n = 1311)	-1.1 ± 6.49
Change from BL at Cycle 6 (n = 1248)	-1.5 ± 6.60
Change from BL at Cycle 9 (n = 1150)	-2.1 ± 6.56
Change from BL at Cycle 12 (n = 1028)	-1.9 ± 6.66
Change from BL at Cycle 15 (n = 898)	-2.2 ± 6.50
Change from BL at Cycle 18 (n = 816)	-1.8 ± 6.77
Change from BL at Cycle 21 (n = 731)	-1.9 ± 6.79
Change from BL at Cycle 24 (n = 681)	-1.9 ± 6.93
Change from BL at Cycle 27 (n = 633)	-2.1 ± 6.81
Change from BL at Cycle 30 (n = 589)	-1.8 ± 6.80
Change from BL at Cycle 33 (n = 558)	-1.9 ± 6.97
Change from BL at Cycle 36 (n = 509)	-2.1 ± 6.53
Change from BL at Cycle 39 (n = 480)	-2.1 ± 6.77
Change from BL at Cycle 42 (n = 451)	-1.9 ± 6.52
Change from BL at Cycle 45 (n = 428)	-2.2 ± 6.94
Change from BL at Cycle 48 (n = 390)	-2.1 ± 6.67
Change from BL at Cycle 51 (n = 357)	-1.6 ± 6.75
Change from BL at Cycle 54 (n = 325)	-1.7 ± 6.38
Change from BL at Cycle 57 (n = 332)	-1.7 ± 6.87
Change from BL at Cycle 60 (n = 313)	-1.5 ± 6.46
Change from BL at Cycle 63 (n = 302)	-1.6 ± 7.13
Change from BL at Cycle 66 (n = 284)	-2.0 ± 6.63
Change from BL at Cycle 69 (n = 270)	-1.9 ± 6.45
Change from BL at Cycle 72 (n = 259)	-2.1 ± 6.80
Change from BL at Cycle 75 (n = 254)	-1.5 ± 6.84
Change from BL at Cycle 78 (n = 245)	-1.8 ± 7.41
Change from BL at Cycle 81 (n = 226)	-1.8 ± 6.98
Change from BL at Cycle 84 (n = 215)	-1.6 ± 6.89
Change from BL at Cycle 87 (n = 196)	-1.9 ± 6.31
Change from BL at Cycle 90 (n = 177)	-1.1 ± 6.68
Change from BL at Cycle 93 (n = 156)	-1.6 ± 6.78
Change from BL at Cycle 96 (n = 128)	-1.8 ± 6.33
Change from BL at Cycle 99 (n = 106)	-2.0 ± 7.20
Change from BL at Cycle 102 (n = 82)	-2.5 ± 7.95
Change from BL at Cycle 105 (n = 65)	-2.5 ± 6.86
Change from BL at Cycle 108 (n = 49)	-1.8 ± 8.04
Change from BL at Cycle 111 (n = 42)	-3.3 ± 7.47
Change from BL at Cycle 114 (n = 23)	-1.1 ± 8.12
Change from BL at Cycle 117 (n = 17)	-5.8 ± 7.48
Change from BL at Cycle 120 (n = 7)	-8.6 ± 6.70
Change from BL at Cycle 123 (n = 3)	-9.3 ± 3.51
Change from BL at Cycle 126 (n = 1)	-9.0 ± 999999
Change from BL at End of Treatment (n = 546)	-3.8 ± 8.34
Change from BL at Day 28 of Follow-Up (n = 584)	-3.2 ± 8.19
Change from BL: Final Treatment Value (n = 1360)	-2.0 ± 6.77
Change from BL: Worst Treatment Value (n = 1360)	-7.1 ± 6.88
Change from BL: Maximum Decrease Value (n = 1398)	-7.7 ± 7.45

Notes
[24] - '999999' means the standard deviation could not be calculated with data from a single participant.

No statistical analyses for this end point

Primary: Number of Participants by Change from Baseline in Left Ventricular Ejection Fraction (LVEF) Categories Over the Course of the Study

Top of page

End point title

Number of Participants by Change from Baseline in Left Ventricular Ejection Fraction (LVEF) Categories Over the Course of the Study ^[25]

End point description

All participants must have had a baseline LVEF greater than or equal to (≥)50% to enroll in the study; patients with significant cardiac disease or baseline LVEF below 50% were not eligible for this study. The number of participants are reported according to four change from baseline in LVEF value categories over the course of the study: 1) an increase or decrease from baseline LVEF less than (<)10% points or no change in LVEF; 2) an absolute LVEF value <45% points and a decrease from baseline LVEF ≥10% points to <15% points; 3) an absolute LVEF value <45% points and a decrease from baseline LVEF ≥15% points; or 4) an absolute LVEF value ≥45% points and a decrease from baseline LVEF ≥10% points. BL = baseline; Cyc = cycle; D28FU = Day 28 of follow-up; Dec = decrease; EOT = end of treatment; Inc = increase

End point type

Primary

End point timeframe

Notes
[25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Cyc3: Inc/Dec from BL<10% or No Change (n=1311)	1190
Cyc3: LVEF<45% and Dec from BL ≥10%–<15% (n=1311)	2
Cyc3: LVEF<45% and Dec from BL ≥15% (n=1311)	5
Cyc3: LVEF ≥45% and Dec from BL ≥10% (n=1311)	114
Cyc6: Inc/Dec from BL<10% or No Change (n=1248)	1110
Cyc6: LVEF<45% and Dec from BL ≥10%–<15% (n=1248)	0
Cyc6: LVEF<45% and Dec from BL ≥15% (n=1248)	2
Cyc6: LVEF ≥45% and Dec from BL ≥10% (n=1248)	136
Cyc9: Inc/Dec from BL<10% or No Change (n=1150)	1005
Cyc9: LVEF<45% and Dec from BL ≥10%–<15% (n=1150)	2
Cyc9: LVEF<45% and Dec from BL ≥15% (n=1150)	4
Cyc9: LVEF ≥45% and Dec from BL ≥10% (n=1150)	139
Cyc12: Inc/Dec from BL<10% or No Change (n=1028)	906
Cyc12: LVEF<45% and Dec from BL ≥10%–<15% (n=1028)	0
Cyc12: LVEF<45% and Dec from BL ≥15% (n=1028)	6
Cyc12: LVEF ≥45% and Dec from BL ≥10% (n=1028)	116
Cyc15: Inc/Dec from BL<10% or No Change (n=898)	780
Cyc15: LVEF<45% and Dec from BL ≥10%–<15% (n=898)	3
Cyc15: LVEF<45% and Dec from BL ≥15% (n=898)	6
Cyc15: LVEF ≥45% and Dec from BL ≥10% (n=898)	109
Cyc18: Inc/Dec from BL<10% or No Change (n=816)	719
Cyc18: LVEF<45% and Dec from BL ≥10%–<15% (n=816)	0
Cyc18: LVEF<45% and Dec from BL ≥15% (n=816)	5
Cyc18: LVEF ≥45% and Dec from BL ≥10% (n=816)	92
Cyc21: Inc/Dec from BL<10% or No Change (n=731)	639
Cyc21: LVEF<45% and Dec from BL ≥10%–<15% (n=731)	0
Cyc21: LVEF<45% and Dec from BL ≥15% (n=731)	4
Cyc21: LVEF ≥45% and Dec from BL ≥10% (n=731)	88
Cyc24: Inc/Dec from BL<10% or No Change (n=681)	588
Cyc24: LVEF<45% and Dec from BL ≥10%–<15% (n=681)	0
Cyc24: LVEF<45% and Dec from BL ≥15% (n=681)	2
Cyc24: LVEF ≥45% and Dec from BL ≥10% (n=681)	91
Cyc27: Inc/Dec from BL<10% or No Change (n=633)	553
Cyc27: LVEF<45% and Dec from BL ≥10%–<15% (n=633)	0
Cyc27: LVEF<45% and Dec from BL ≥15% (n=633)	2
Cyc27: LVEF ≥45% and Dec from BL ≥10% (n=633)	78
Cyc30: Inc/Dec from BL<10% or No Change (n=589)	518
Cyc30: LVEF<45% and Dec from BL ≥10%–<15% (n=589)	0
Cyc30: LVEF<45% and Dec from BL ≥15% (n=589)	1
Cyc30: LVEF ≥45% and Dec from BL ≥10% (n=589)	70
Cyc33: Inc/Dec from BL<10% or No Change (n=558)	485
Cyc33: LVEF<45% and Dec from BL ≥10%–<15% (n=558)	0
Cyc33: LVEF<45% and Dec from BL ≥15% (n=558)	1
Cyc33: LVEF ≥45% and Dec from BL ≥10% (n=558)	72
Cyc36: Inc/Dec from BL<10% or No Change (n=509)	446
Cyc36: LVEF<45% and Dec from BL ≥10%–<15% (n=509)	0
Cyc36: LVEF<45% and Dec from BL ≥15% (n=509)	1
Cyc36: LVEF ≥45% and Dec from BL ≥10% (n=509)	62
Cyc39: Inc/Dec from BL<10% or No Change (n=480)	414
Cyc39: LVEF<45% and Dec from BL ≥10%–<15% (n=480)	1
Cyc39: LVEF<45% and Dec from BL ≥15% (n=480)	0
Cyc39: LVEF ≥45% and Dec from BL ≥10% (n=480)	65
Cyc42: Inc/Dec from BL<10% or No Change (n=451)	405
Cyc42: LVEF<45% and Dec from BL ≥10%–<15% (n=451)	0
Cyc42: LVEF<45% and Dec from BL ≥15% (n=451)	0
Cyc42: LVEF ≥45% and Dec from BL ≥10% (n=451)	46
Cyc45: Inc/Dec from BL<10% or No Change (n=428)	358
Cyc45: LVEF<45% and Dec from BL ≥10%–<15% (n=428)	0
Cyc45: LVEF<45% and Dec from BL ≥15% (n=428)	1
Cyc45: LVEF ≥45% and Dec from BL ≥10% (n=428)	69
Cyc48: Inc/Dec from BL<10% or No Change (n=390)	340
Cyc48: LVEF<45% and Dec from BL ≥10%–<15% (n=390)	0
Cyc48: LVEF<45% and Dec from BL ≥15% (n=390)	1
Cyc48: LVEF ≥45% and Dec from BL ≥10% (n=390)	49
Cyc51: Inc/Dec from BL<10% or No Change (n=357)	314
Cyc51: LVEF<45% and Dec from BL ≥10%–<15% (n=357)	0
Cyc51: LVEF<45% and Dec from BL ≥15% (n=357)	0
Cyc51: LVEF ≥45% and Dec from BL ≥10% (n=357)	43
Cyc54: Inc/Dec from BL<10% or No Change (n=325)	292
Cyc54: LVEF<45% and Dec from BL ≥10%–<15% (n=325)	0
Cyc54: LVEF<45% and Dec from BL ≥15% (n=325)	3
Cyc54: LVEF ≥45% and Dec from BL ≥10% (n=325)	30
Cyc57: Inc/Dec from BL<10% or No Change (n=332)	291
Cyc57: LVEF<45% and Dec from BL ≥10%–<15% (n=332)	0
Cyc57: LVEF<45% and Dec from BL ≥15% (n=332)	0
Cyc57: LVEF ≥45% and Dec from BL ≥10% (n=332)	41
Cyc60: Inc/Dec from BL<10% or No Change (n=313)	284
Cyc60: LVEF<45% and Dec from BL ≥10%–<15% (n=313)	0
Cyc60: LVEF<45% and Dec from BL ≥15% (n=313)	0
Cyc60: LVEF ≥45% and Dec from BL ≥10% (n=313)	29
Cyc63: Inc/Dec from BL<10% or No Change (n=302)	263
Cyc63: LVEF<45% and Dec from BL ≥10%–<15% (n=302)	0
Cyc63: LVEF<45% and Dec from BL ≥15% (n=302)	0
Cyc63: LVEF ≥45% and Dec from BL ≥10% (n=302)	39
Cyc66: Inc/Dec from BL<10% or No Change (n=284)	249
Cyc66: LVEF<45% and Dec from BL ≥10%–<15% (n=284)	0
Cyc66: LVEF<45% and Dec from BL ≥15% (n=284)	0
Cyc66: LVEF ≥45% and Dec from BL ≥10% (n=284)	35
Cyc69: Inc/Dec from BL<10% or No Change (n=270)	237
Cyc69: LVEF<45% and Dec from BL ≥10%–<15% (n=270)	0
Cyc69: LVEF<45% and Dec from BL ≥15% (n=270)	0
Cyc69: LVEF ≥45% and Dec from BL ≥10% (n=270)	33
Cyc72: Inc/Dec from BL<10% or No Change (n=259)	224
Cyc72: LVEF<45% and Dec from BL ≥10%–<15% (n=259)	0
Cyc72: LVEF<45% and Dec from BL ≥15% (n=259)	0
Cyc72: LVEF ≥45% and Dec from BL ≥10% (n=259)	35
Cyc75: Inc/Dec from BL<10% or No Change (n=254)	224
Cyc75: LVEF<45% and Dec from BL ≥10%–<15% (n=254)	0
Cyc75: LVEF<45% and Dec from BL ≥15% (n=254)	1
Cyc75: LVEF ≥45% and Dec from BL ≥10% (n=254)	29
Cyc78: Inc/Dec from BL<10% or No Change (n=245)	214
Cyc78: LVEF<45% and Dec from BL ≥10%–<15% (n=245)	0
Cyc78: LVEF<45% and Dec from BL ≥15% (n=245)	2
Cyc78: LVEF ≥45% and Dec from BL ≥10% (n=245)	29
Cyc81: Inc/Dec from BL<10% or No Change (n=226)	196
Cyc81: LVEF<45% and Dec from BL ≥10%–<15% (n=226)	0
Cyc81: LVEF<45% and Dec from BL ≥15% (n=226)	0
Cyc81: LVEF ≥45% and Dec from BL ≥10% (n=226)	30
Cyc84: Inc/Dec from BL<10% or No Change (n=215)	192
Cyc84: LVEF<45% and Dec from BL ≥10%–<15% (n=215)	0
Cyc84: LVEF<45% and Dec from BL ≥15% (n=215)	0
Cyc84: LVEF ≥45% and Dec from BL ≥10% (n=215)	23
Cyc87: Inc/Dec from BL<10% or No Change (n=196)	174
Cyc87: LVEF<45% and Dec from BL ≥10%–<15% (n=196)	0
Cyc87: LVEF<45% and Dec from BL ≥15% (n=196)	0
Cyc87: LVEF ≥45% and Dec from BL ≥10% (n=196)	22
Cyc90: Inc/Dec from BL<10% or No Change (n=177)	161
Cyc90: LVEF<45% and Dec from BL ≥10%–<15% (n=177)	0
Cyc90: LVEF<45% and Dec from BL ≥15% (n=177)	0
Cyc90: LVEF ≥45% and Dec from BL ≥10% (n=177)	16
Cyc93: Inc/Dec from BL<10% or No Change (n=156)	140
Cyc93: LVEF<45% and Dec from BL ≥10%–<15% (n=156)	0
Cyc93: LVEF<45% and Dec from BL ≥15% (n=156)	0
Cyc93: LVEF ≥45% and Dec from BL ≥10% (n=156)	16
Cyc96: Inc/Dec from BL<10% or No Change (n=128)	115
Cyc96: LVEF<45% and Dec from BL ≥10%–<15% (n=128)	0
Cyc96: LVEF<45% and Dec from BL ≥15% (n=128)	0
Cyc96: LVEF ≥45% and Dec from BL ≥10% (n=128)	13
Cyc99: Inc/Dec from BL<10% or No Change (n=106)	92
Cyc99: LVEF<45% and Dec from BL ≥10%–<15% (n=106)	0
Cyc99: LVEF<45% and Dec from BL ≥15% (n=106)	0
Cyc99: LVEF ≥45% and Dec from BL ≥10% (n=106)	14
Cyc102: Inc/Dec from BL<10% or No Change (n=82)	68
Cyc102: LVEF<45% and Dec from BL ≥10%–<15% (n=82)	0
Cyc102: LVEF<45% and Dec from BL ≥15% (n=82)	0
Cyc102: LVEF ≥45% and Dec from BL ≥10% (n=82)	14
Cyc105: Inc/Dec from BL<10% or No Change (n=65)	56
Cyc105: LVEF<45% and Dec from BL ≥10%–<15% (n=65)	0
Cyc105: LVEF<45% and Dec from BL ≥15% (n=65)	0
Cyc105: LVEF ≥45% and Dec from BL ≥10% (n=65)	9
Cyc108: Inc/Dec from BL<10% or No Change (n=49)	41
Cyc108: LVEF<45% and Dec from BL ≥10%–<15% (n=49)	0
Cyc108: LVEF<45% and Dec from BL ≥15% (n=49)	0
Cyc108: LVEF ≥45% and Dec from BL ≥10% (n=49)	8
Cyc111: Inc/Dec from BL<10% or No Change (n=42)	34
Cyc111: LVEF<45% and Dec from BL ≥10%–<15% (n=42)	0
Cyc111: LVEF<45% and Dec from BL ≥15% (n=42)	0
Cyc111: LVEF ≥45% and Dec from BL ≥10% (n=42)	8
Cyc114: Inc/Dec from BL<10% or No Change (n=23)	19
Cyc114: LVEF<45% and Dec from BL ≥10%–<15% (n=23)	0
Cyc114: LVEF<45% and Dec from BL ≥15% (n=23)	0
Cyc114: LVEF ≥45% and Dec from BL ≥10% (n=23)	4
Cyc117: Inc/Dec from BL<10% or No Change (n=17)	11
Cyc117: LVEF<45% and Dec from BL ≥10%–<15% (n=17)	0
Cyc117: LVEF<45% and Dec from BL ≥15% (n=17)	0
Cyc117: LVEF ≥45% and Dec from BL ≥10% (n=17)	6
Cyc120: Inc/Dec from BL<10% or No Change (n=7)	4
Cyc120: LVEF<45% and Dec from BL ≥10%–<15% (n=7)	0
Cyc120: LVEF<45% and Dec from BL ≥15% (n=7)	0
Cyc120: LVEF ≥45% and Dec from BL ≥10% (n=7)	3
Cyc123: Inc/Dec from BL<10% or No Change (n=3)	2
Cyc123: LVEF<45% and Dec from BL ≥10%–<15% (n=3)	0
Cyc123: LVEF<45% and Dec from BL ≥15% (n=3)	0
Cyc123: LVEF ≥45% and Dec from BL ≥10% (n=3)	1
Cyc126: Inc/Dec from BL<10% or No Change (n=1)	1
Cyc126: LVEF<45% and Dec from BL ≥10%–<15% (n=1)	0
Cyc126: LVEF<45% and Dec from BL ≥15% (n=1)	0
Cyc126: LVEF ≥45% and Dec from BL ≥10% (n=1)	0
EOT: Inc/Dec from BL<10% or No Change (n=546)	431
EOT: LVEF<45% and Dec from BL ≥10%–<15% (n=546)	2
EOT: LVEF<45% and Dec from BL ≥15% (n=546)	26
EOT: LVEF ≥45% and Dec from BL ≥10% (n=546)	87
D28FU: Inc/Dec from BL<10% or No Change (n=584)	472
D28FU: LVEF<45% and Dec from BL ≥10%–<15% (n=584)	4
D28FU: LVEF<45% and Dec from BL ≥15% (n=584)	22
D28FU: LVEF ≥45% and Dec from BL ≥10% (n=584)	86

No statistical analyses for this end point

Primary: Number of Participants with Laboratory Abnormalities in Hematology and Coagulation Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to NCI-CTC v4.0

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End point title

Number of Participants with Laboratory Abnormalities in Hematology and Coagulation Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to NCI-CTC v4.0 ^[26]

End point description

Clinical laboratory tests for hematology and coagulation parameters were performed at local laboratories. Laboratory toxicities were defined based on NCI-CTC v4.0 from Grades 1 (least severe) to 4 (most severe). Some laboratory parameters are bi-dimensional (i.e. can be graded in both the low and high direction). These parameters were split and presented in both directions. Baseline was defined as the last non-missing measurement taken prior to the first dose of study treatment (including unscheduled assessments). Values from all visits, including unscheduled visits, were included in the derivation of the worst post-baseline grade. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: was clinically significant (per investigator); was accompanied by clinical symptoms; resulted in a change in study treatment; or resulted in a medical intervention or a change in concomitant therapy.

End point type

Primary

End point timeframe

Predose for each treatment cycle (1 cycle is 3 weeks) from Baseline until 28 days after the last dose of study treatment. The median (full range) duration of exposure to any study treatment was 16.2 (0.0-86.4) months.

Notes
[26] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Absolute Neutrophil Count: Normal to Normal	844
Absolute Neutrophil Count: Normal to Grade 1	232
Absolute Neutrophil Count: Normal to Grade 2	169
Absolute Neutrophil Count: Normal to Grade 3	45
Absolute Neutrophil Count: Normal to Grade 4	27
Absolute Neutrophil Count: Normal to Missing	27
Absolute Neutrophil Count: Grade 1 to Normal	3
Absolute Neutrophil Count: Grade 1 to 1	11
Absolute Neutrophil Count: Grade 1 to 2	14
Absolute Neutrophil Count: Grade 1 to 3	3
Absolute Neutrophil Count: Grade 2 to 1	2
Absolute Neutrophil Count: Missing to Normal	21
Absolute Neutrophil Count: Missing to Grade 1	2
Absolute Neutrophil Count: Missing to Grade 2	3
Absolute Neutrophil Count: Missing to Grade 4	1
Absolute Neutrophil Count: Missing to Missing	32
Hemoglobin (High): Normal to Normal	1327
Hemoglobin (High): Normal to Grade 1	29
Hemoglobin (High): Normal to Grade 3	1
Hemoglobin (High): Normal to Missing	26
Hemoglobin (High): Grade 1 to Normal	28
Hemoglobin (High): Grade 1 to 1	5
Hemoglobin (High): Grade 1 to Missing	2
Hemoglobin (High): Grade 2 to Normal	1
Hemoglobin (High): Missing to Normal	14
Hemoglobin (High): Missing to Missing	3
Hemoglobin (Low): Normal to Normal	257
Hemoglobin (Low): Normal to Grade 1	648
Hemoglobin (Low): Normal to Grade 2	198
Hemoglobin (Low): Normal to Grade 3	10
Hemoglobin (Low): Normal to Missing	21
Hemoglobin (Low): Grade 1 to Normal	2
Hemoglobin (Low): Grade 1 to 1	109
Hemoglobin (Low): Grade 1 to 2	128
Hemoglobin (Low): Grade 1 to 3	12
Hemoglobin (Low): Grade 1 to Missing	4
Hemoglobin (Low): Grade 2 to 1	5
Hemoglobin (Low): Grade 2 to 2	18
Hemoglobin (Low): Grade 2 to 3	3
Hemoglobin (Low): Grade 2 to Missing	3
Hemoglobin (Low): Grade 3 to 1	1
Hemoglobin (Low): Missing to Normal	3
Hemoglobin (Low): Missing to Grade 1	7
Hemoglobin (Low): Missing to Grade 2	4
Hemoglobin (Low): Missing to Missing	3
Lymphocytes (High): Normal to Normal	1251
Lymphocytes (High): Normal to Grade 2	111
Lymphocytes (High): Normal to Grade 3	8
Lymphocytes (High): Normal to Missing	28
Lymphocytes (High): Grade 2 to Normal	4
Lymphocytes (High): Grade 2 to 2	10
Lymphocytes (High): Grade 2 to 3	2
Lymphocytes (High): Grade 3 to Normal	1
Lymphocytes (High): Grade 3 to 3	2
Lymphocytes (High): Missing to Normal	15
Lymphocytes (High): Missing to Grade 2	2
Lymphocytes (High): Missing to Missing	2
Lymphocytes (Low): Normal to Normal	565
Lymphocytes (Low): Normal to Grade 1	255
Lymphocytes (Low): Normal to Grade 2	210
Lymphocytes (Low): Normal to Grade 3	76
Lymphocytes (Low): Normal to Grade 4	18
Lymphocytes (Low): Normal to Missing	19
Lymphocytes (Low): Grade 1 to Normal	11
Lymphocytes (Low): Grade 1 to 1	54
Lymphocytes (Low): Grade 1 to 2	51
Lymphocytes (Low): Grade 1 to 3	18
Lymphocytes (Low): Grade 1 to 4	6
Lymphocytes (Low): Grade 1 to Missing	5
Lymphocytes (Low): Grade 2 to Normal	12
Lymphocytes (Low): Grade 2 to 1	8
Lymphocytes (Low): Grade 2 to 2	37
Lymphocytes (Low): Grade 2 to 3	19
Lymphocytes (Low): Grade 2 to 4	1
Lymphocytes (Low): Grade 2 to Missing	2
Lymphocytes (Low): Grade 3 to 1	3
Lymphocytes (Low): Grade 3 to 2	8
Lymphocytes (Low): Grade 3 to 3	14
Lymphocytes (Low): Grade 3 to 4	2
Lymphocytes (Low): Grade 3 to Missing	1
Lymphocytes (Low): Grade 4 to 2	1
Lymphocytes (Low): Grade 4 to 3	3
Lymphocytes (Low): Grade 4 to 4	16
Lymphocytes (Low): Grade 4 to Missing	1
Lymphocytes (Low): Missing to Normal	11
Lymphocytes (Low): Missing to Grade 1	3
Lymphocytes (Low): Missing to Grade 2	3
Lymphocytes (Low): Missing to Grade 3	1
Lymphocytes (Low): Missing to Missing	2
Platelet Count: Normal to Normal	1222
Platelet Count: Normal to Grade 1	149
Platelet Count: Normal to Grade 3	1
Platelet Count: Normal to Grade 4	2
Platelet Count: Normal to Missing	26
Platelet Count: Grade 1 to Normal	15
Platelet Count: Grade 1 to 1	16
Platelet Count: Grade 1 to 2	1
Platelet Count: Grade 1 to Missing	2
Platelet Count: Missing to Normal	1
Platelet Count: Missing to Grade 1	1
White Blood Cells (High): Normal to Normal	1391
White Blood Cells (High): Normal to Missing	29
White Blood Cells (High): Missing to Normal	14
White Blood Cells (High): Missing to Missing	2
White Blood Cells (Low): Normal to Normal	702
White Blood Cells (Low): Normal to Grade 1	392
White Blood Cells (Low): Normal to Grade 2	190
White Blood Cells (Low): Normal to Grade 3	29
White Blood Cells (Low): Normal to Grade 4	6
White Blood Cells (Low): Normal to Missing	29
White Blood Cells (Low): Grade 1 to Normal	4
White Blood Cells (Low): Grade 1 to 1	20
White Blood Cells (Low): Grade 1 to 2	33
White Blood Cells (Low): Grade 1 to 3	4
White Blood Cells (Low): Grade 2 to Normal	2
White Blood Cells (Low): Grade 2 to 1	4
White Blood Cells (Low): Grade 2 to 2	3
White Blood Cells (Low): Grade 3 to Normal	1
White Blood Cells (Low): Grade 3 to 3	1
White Blood Cells (Low): Missing to Normal	9
White Blood Cells (Low): Missing to Grade 1	3
White Blood Cells (Low): Missing to Grade 2	1
White Blood Cells (Low): Missing to Grade 3	1
White Blood Cells (Low): Missing to Missing	2
International Normalized Ratio: Normal to Normal	17
International Normalized Ratio: Normal to Grade 1	52
International Normalized Ratio: Normal to Grade 2	1
International Normalized Ratio: Normal to Missing	3
International Normalized Ratio: Grade 1 to Normal	1
International Normalized Ratio: Grade 2 to 3	1
International Normalized Ratio: Missing to Normal	424
International Normalized Ratio: Missing to Grade 1	615
International Normalized Ratio: Missing to Grade 2	23
International Normalized Ratio: Missing to Grade 3	14
International Normalized Ratio: Missing to Missing	285

No statistical analyses for this end point

Primary: Number of Participants with Laboratory Abnormalities in Hematology and Coagulation Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to Normal Range Criteria

Top of page

End point title

Number of Participants with Laboratory Abnormalities in Hematology and Coagulation Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to Normal Range Criteria ^[27]

End point description

Clinical laboratory tests for hematology and coagulation parameters were performed at local laboratories. Laboratory toxicities were defined based on local laboratory normal ranges (for parameters with NCI-CTC grade not defined). Some laboratory parameters are bi-dimensional (i.e. can be graded in both the low and high direction). These parameters were split and presented in both directions. Baseline was defined as the last non-missing measurement taken prior to the first dose of study treatment (including unscheduled assessments). Values from all visits, including unscheduled visits, were included in the derivation of the worst post-baseline grade. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: was clinically significant (per investigator); was accompanied by clinical symptoms; resulted in a change in study treatment; or resulted in a medical intervention or a change in concomitant therapy.

End point type

Primary

End point timeframe

Notes
[27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Basophils (High): Normal to Normal	1020
Basophils (High): Normal to Low	3
Basophils (High): Normal to High	261
Basophils (High): Low to Normal	16
Basophils (High): Low to Low	1
Basophils (High): Low to High	5
Basophils (High): High to Normal	11
Basophils (High): High to High	38
Basophils (High): Missing to Normal	21
Basophils (High): Missing to High	7
Basophils (High): Missing to Missing	53
Basophils (Low): Normal to Normal	1206
Basophils (Low): Normal to Low	77
Basophils (Low): Normal to High	1
Basophils (Low): Low to Normal	3
Basophils (Low): Low to Low	18
Basophils (Low): Low to Missing	1
Basophils (Low): High to Normal	36
Basophils (Low): High to Low	5
Basophils (Low): High to High	8
Basophils (Low): Missing to Normal	40
Basophils (Low): Missing to Low	3
Basophils (Low): Missing to High	1
Basophils (Low): Missing to Missing	37
Eosinophils (High): Normal to Normal	904
Eosinophils (High): Normal to Low	13
Eosinophils (High): Normal to High	283
Eosinophils (High): Low to Normal	66
Eosinophils (High): Low to Low	13
Eosinophils (High): Low to High	36
Eosinophils (High): High to Normal	11
Eosinophils (High): High to High	35
Eosinophils (High): Missing to Normal	17
Eosinophils (High): Missing to Low	1
Eosinophils (High): Missing to High	7
Eosinophils (High): Missing to Missing	50
Eosinophils (Low): Normal to Normal	810
Eosinophils (Low): Normal to Low	390
Eosinophils (Low): Low to Normal	13
Eosinophils (Low): Low to Low	101
Eosinophils (Low): Low to High	1
Eosinophils (Low): High to Normal	28
Eosinophils (Low): High to Low	13
Eosinophils (Low): High to High	5
Eosinophils (Low): Missing to Normal	37
Eosinophils (Low): Missing to Low	10
Eosinophils (Low): Missing to Missing	28
Hematocrit (High): Normal to Normal	953
Hematocrit (High): Normal to Low	47
Hematocrit (High): Normal to High	58
Hematocrit (High): Normal to Missing	4
Hematocrit (High): Low to Normal	201
Hematocrit (High): Low to Low	97
Hematocrit (High): Low to High	10
Hematocrit (High): Low to Missing	2
Hematocrit (High): High to Normal	17
Hematocrit (High): High to High	12
Hematocrit (High): Missing to Normal	15
Hematocrit (High): Missing to High	1
Hematocrit (High): Missing to Missing	19
Hematocrit (Low): Normal to Normal	223
Hematocrit (Low): Normal to Low	837
Hematocrit (Low): Normal to Missing	2
Hematocrit (Low): Low to Normal	5
Hematocrit (Low): Low to Low	305
Hematocrit (Low): High to Normal	13
Hematocrit (Low): High to Low	16
Hematocrit (Low): Missing to Normal	3
Hematocrit (Low): Missing to Low	12
Hematocrit (Low): Missing to Missing	20
Monocytes (High): Normal to Normal	802
Monocytes (High): Normal to Low	3
Monocytes (High): Normal to High	365
Monocytes (High): Low to Normal	58
Monocytes (High): Low to Low	6
Monocytes (High): Low to High	17
Monocytes (High): High to Normal	29
Monocytes (High): High to Low	1
Monocytes (High): High to High	82
Monocytes (High): Missing to Normal	12
Monocytes (High): Missing to High	8
Monocytes (High): Missing to Missing	53
Monocytes (Low): Normal to Normal	747
Monocytes (Low): Normal to Low	420
Monocytes (Low): Normal to High	3
Monocytes (Low): Low to Normal	11
Monocytes (Low): Low to Low	70
Monocytes (Low): High to Normal	64
Monocytes (Low): High to Low	40
Monocytes (Low): High to High	8
Monocytes (Low): Missing to Normal	13
Monocytes (Low): Missing to Low	10
Monocytes (Low): Missing to High	5
Monocytes (Low): Missing to Missing	45
Red Blood Cells (High): Normal to Normal	975
Red Blood Cells (High): Normal to Low	31
Red Blood Cells (High): Normal to High	111
Red Blood Cells (High): Low to Normal	131
Red Blood Cells (High): Low to Low	61
Red Blood Cells (High): Low to High	15
Red Blood Cells (High): High to Normal	22
Red Blood Cells (High): High to High	45
Red Blood Cells (High): Missing to Normal	18
Red Blood Cells (High): Missing to Low	2
Red Blood Cells (High): Missing to High	2
Red Blood Cells (High): Missing to Missing	23
Red Blood Cells (Low): Normal to Normal	350
Red Blood Cells (Low): Normal to Low	767
Red Blood Cells (Low): Low to Normal	10
Red Blood Cells (Low): Low to Low	197
Red Blood Cells (Low): High to Normal	44
Red Blood Cells (Low): High to Low	21
Red Blood Cells (Low): High to High	2
Red Blood Cells (Low): Missing to Normal	6
Red Blood Cells (Low): Missing to Low	16
Red Blood Cells (Low): Missing to Missing	23
PTT (High): Normal to Normal	46
PTT (High): Normal to Low	1
PTT (High): Normal to High	15
PTT (High): Low to Normal	19
PTT (High): Low to Low	1
PTT (High): Low to High	1
PTT (High): High to High	1
PTT (High): Missing to Normal	19
PTT (High): Missing to Low	5
PTT (High): Missing to High	9
PTT (High): Missing to Missing	1319
PTT (Low): Normal to Normal	46
PTT (Low): Normal to Low	16
PTT (Low): Low to Normal	3
PTT (Low): Low to Low	18
PTT (Low): High to Normal	1
PTT (Low): Missing to Normal	20
PTT (Low): Missing to Low	6
PTT (Low): Missing to High	5
PTT (Low): Missing to Missing	1321

No statistical analyses for this end point

Primary: Number of Participants with Laboratory Abnormalities in Biochemistry Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to NCI-CTC v4.0

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End point title

Number of Participants with Laboratory Abnormalities in Biochemistry Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to NCI-CTC v4.0 ^[28]

End point description

Clinical laboratory tests for biochemistry parameters were performed at local laboratories. Laboratory toxicities were defined based on NCI-CTC v4.0 from Grades 1 (least severe) to 4 (most severe). Some laboratory parameters are bi-dimensional (i.e. can be graded in both the low and high direction). These parameters were split and presented in both directions. Baseline was defined as the last non-missing measurement taken prior to the first dose of study treatment (including unscheduled assessments). Values from all visits, including unscheduled visits, were included in the derivation of the worst post-baseline grade. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: was clinically significant (per investigator); was accompanied by clinical symptoms; resulted in a change in study treatment; or resulted in a medical intervention or a change in concomitant therapy.

End point type

Primary

End point timeframe

Notes
[28] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Alanine Aminotransferase: Normal to Normal	610
Alanine Aminotransferase: Normal to Grade 1	425
Alanine Aminotransferase: Normal to Grade 2	26
Alanine Aminotransferase: Normal to Grade 3	19
Alanine Aminotransferase: Normal to Missing	25
Alanine Aminotransferase: Grade 1 to Normal	75
Alanine Aminotransferase: Grade 1 to 1	151
Alanine Aminotransferase: Grade 1 to 2	26
Alanine Aminotransferase: Grade 1 to 3	14
Alanine Aminotransferase: Grade 1 to Missing	6
Alanine Aminotransferase: Grade 2 to Normal	8
Alanine Aminotransferase: Grade 2 to 1	28
Alanine Aminotransferase: Grade 2 to 2	5
Alanine Aminotransferase: Grade 2 to 3	1
Alanine Aminotransferase: Grade 3 to 1	2
Alanine Aminotransferase: Missing to Normal	7
Alanine Aminotransferase: Missing to Grade 1	4
Alanine Aminotransferase: Missing to Grade 2	1
Alanine Aminotransferase: Missing to Missing	3
Aspartate Aminotransferase: Normal to Normal	562
Aspartate Aminotransferase: Normal to Grade 1	386
Aspartate Aminotransferase: Normal to Grade 2	22
Aspartate Aminotransferase: Normal to Grade 3	9
Aspartate Aminotransferase: Normal to Missing	15
Aspartate Aminotransferase: Grade 1 to Normal	120
Aspartate Aminotransferase: Grade 1 to 1	187
Aspartate Aminotransferase: Grade 1 to 2	24
Aspartate Aminotransferase: Grade 1 to 3	9
Aspartate Aminotransferase: Grade 1 to Missing	14
Aspartate Aminotransferase: Grade 2 to Normal	13
Aspartate Aminotransferase: Grade 2 to 1	29
Aspartate Aminotransferase: Grade 2 to 2	3
Aspartate Aminotransferase: Grade 2 to Missing	3
Aspartate Aminotransferase: Grade 3 to Normal	2
Aspartate Aminotransferase: Grade 3 to 1	7
Aspartate Aminotransferase: Grade 3 to Missing	1
Aspartate Aminotransferase: Missing to Normal	13
Aspartate Aminotransferase: Missing to Grade 1	9
Aspartate Aminotransferase: Missing to Grade 2	2
Aspartate Aminotransferase: Missing to Missing	6
Albumin: Normal to Normal	785
Albumin: Normal to Grade 1	357
Albumin: Normal to Grade 2	86
Albumin: Normal to Grade 3	10
Albumin: Normal to Missing	23
Albumin: Grade 1 to Normal	13
Albumin: Grade 1 to 1	43
Albumin: Grade 1 to 2	35
Albumin: Grade 1 to 3	1
Albumin: Grade 1 to Missing	7
Albumin: Grade 2 to Normal	3
Albumin: Grade 2 to 1	5
Albumin: Grade 2 to 2	8
Albumin: Grade 2 to 3	2
Albumin: Grade 2 to Missing	2
Albumin: Grade 3 to 2	1
Albumin: Grade 3 to Missing	1
Albumin: Missing to Normal	28
Albumin: Missing to Grade 1	14
Albumin: Missing to Grade 2	6
Albumin: Missing to Missing	6
Alkaline Phosphatase: Normal to Normal	605
Alkaline Phosphatase: Normal to Grade 1	329
Alkaline Phosphatase: Normal to Grade 2	14
Alkaline Phosphatase: Normal to Grade 3	2
Alkaline Phosphatase: Normal to Missing	18
Alkaline Phosphatase: Grade 1 to Normal	44
Alkaline Phosphatase: Grade 1 to 1	241
Alkaline Phosphatase: Grade 1 to 2	72
Alkaline Phosphatase: Grade 1 to 3	15
Alkaline Phosphatase: Grade 1 to Missing	6
Alkaline Phosphatase: Grade 2 to Normal	2
Alkaline Phosphatase: Grade 2 to 1	21
Alkaline Phosphatase: Grade 2 to 2	24
Alkaline Phosphatase: Grade 2 to 3	14
Alkaline Phosphatase: Grade 2 to Missing	8
Alkaline Phosphatase: Grade 3 to 1	2
Alkaline Phosphatase: Grade 3 to 2	1
Alkaline Phosphatase: Grade 3 to 3	4
Alkaline Phosphatase: Missing to Normal	7
Alkaline Phosphatase: Missing to Grade 1	3
Alkaline Phosphatase: Missing to Grade 3	1
Alkaline Phosphatase: Missing to Missing	3
Calcium (High): Normal to Normal	1060
Calcium (High): Normal to Grade 1	192
Calcium (High): Normal to Grade 2	2
Calcium (High): Normal to Grade 3	1
Calcium (High): Normal to Grade 4	1
Calcium (High): Normal to Missing	26
Calcium (High): Grade 1 to Normal	47
Calcium (High): Grade 1 to 1	47
Calcium (High): Grade 1 to 2	1
Calcium (High): Grade 1 to 3	1
Calcium (High): Grade 1 to Missing	5
Calcium (High): Grade 2 to Normal	1
Calcium (High): Grade 2 to 1	1
Calcium (High): Grade 2 to 2	1
Calcium (High): Grade 3 to Normal	2
Calcium (High): Grade 3 to 1	1
Calcium (High): Grade 3 to 2	1
Calcium (High): Grade 4 to Normal	1
Calcium (High): Missing to Normal	32
Calcium (High): Missing to Grade 1	3
Calcium (High): Missing to Missing	10
Calcium (Low): Normal to Normal	786
Calcium (Low): Normal to Grade 1	378
Calcium (Low): Normal to Grade 2	117
Calcium (Low): Normal to Grade 3	18
Calcium (Low): Normal to Missing	30
Calcium (Low): Grade 1 to Normal	5
Calcium (Low): Grade 1 to 1	31
Calcium (Low): Grade 1 to 2	12
Calcium (Low): Grade 1 to 3	2
Calcium (Low): Grade 1 to Missing	1
Calcium (Low): Grade 2 to Normal	5
Calcium (Low): Grade 2 to 1	1
Calcium (Low): Grade 2 to 2	4
Calcium (Low): Grade 3 to 3	1
Calcium (Low): Missing to Normal	20
Calcium (Low): Missing to Grade 1	11
Calcium (Low): Missing to Grade 2	4
Calcium (Low): Missing to Missing	10
Creatinine: Normal to Normal	176
Creatinine: Normal to Grade 1	960
Creatinine: Normal to Grade 2	175
Creatinine: Normal to Grade 3	5
Creatinine: Normal to Grade 4	5
Creatinine: Normal to Missing	26
Creatinine: Grade 1 to Normal	12
Creatinine: Grade 1 to 1	38
Creatinine: Grade 1 to 2	8
Creatinine: Grade 1 to Missing	3
Creatinine: Grade 2 to 2	3
Creatinine: Grade 2 to 3	1
Creatinine: Grade 2 to Missing	1
Creatinine: Missing to Normal	11
Creatinine: Missing to Grade 1	6
Creatinine: Missing to Missing	6
Gamma-Glutamyl Transpeptidase: Normal to Normal	498
Gamma-Glutamyl Transpeptidase: Normal to Grade 1	227
Gamma-Glutamyl Transpeptidase: Normal to Grade 2	39
Gamma-Glutamyl Transpeptidase: Normal to Grade 3	15
Gamma-Glutamyl Transpeptidase: Normal to Missing	12
Gamma-Glutamyl Transpeptidase: Grade 1 to Normal	64
Gamma-Glutamyl Transpeptidase: Grade 1 to 1	187
Gamma-Glutamyl Transpeptidase: Grade 1 to 2	75
Gamma-Glutamyl Transpeptidase: Grade 1 to 3	20
Gamma-Glutamyl Transpeptidase: Grade 1 to Missing	7
Gamma-Glutamyl Transpeptidase: Grade 2 to Normal	5
Gamma-Glutamyl Transpeptidase: Grade 2 to 1	52
Gamma-Glutamyl Transpeptidase: Grade 2 to 2	45
Gamma-Glutamyl Transpeptidase: Grade 2 to 3	21
Gamma-Glutamyl Transpeptidase: Grade 2 to Missing	5
Gamma-Glutamyl Transpeptidase: Grade 3 to Normal	2
Gamma-Glutamyl Transpeptidase: Grade 3 to 1	15
Gamma-Glutamyl Transpeptidase: Grade 3 to 2	38
Gamma-Glutamyl Transpeptidase: Grade 3 to 3	47
Gamma-Glutamyl Transpeptidase: Grade 3 to Missing	4
Gamma-Glutamyl Transpeptidase: Missing to Normal	14
Gamma-Glutamyl Transpeptidase: Missing to Grade 1	7
Gamma-Glutamyl Transpeptidase: Missing to Grade 2	10
Gamma-Glutamyl Transpeptidase: Missing to Grade 3	18
Gamma-Glutamyl Transpeptidase: Missing to Missing	9
Glucose (High): Normal to Normal	340
Glucose (High): Normal to Grade 1	534
Glucose (High): Normal to Grade 2	115
Glucose (High): Normal to Missing	21
Glucose (High): Grade 1 to Normal	28
Glucose (High): Grade 1 to 1	190
Glucose (High): Grade 1 to 2	74
Glucose (High): Grade 1 to Missing	9
Glucose (High): Grade 2 to Normal	2
Glucose (High): Grade 2 to 1	13
Glucose (High): Grade 2 to 2	10
Glucose (High): Grade 2 to Missing	3
Glucose (High): Missing to Normal	20
Glucose (High): Missing to Grade 1	30
Glucose (High): Missing to Grade 2	40
Glucose (High): Missing to Missing	7
Glucose (Low): Normal to Normal	1061
Glucose (Low): Normal to Grade 1	173
Glucose (Low): Normal to Grade 2	19
Glucose (Low): Normal to Grade 3	4
Glucose (Low): Normal to Grade 4	5
Glucose (Low): Normal to Missing	33
Glucose (Low): Grade 1 to Normal	8
Glucose (Low): Grade 1 to 1	24
Glucose (Low): Grade 1 to 2	3
Glucose (Low): Grade 1 to 3	1
Glucose (Low): Grade 1 to 4	1
Glucose (Low): Grade 2 to Normal	1
Glucose (Low): Missing to Normal	69
Glucose (Low): Missing to Grade 1	16
Glucose (Low): Missing to Grade 2	2
Glucose (Low): Missing to Grade 3	1
Glucose (Low): Missing to Missing	15
Magnesium (High): Normal to Normal	1100
Magnesium (High): Normal to Grade 1	122
Magnesium (High): Normal to Grade 3	38
Magnesium (High): Normal to Grade 4	6
Magnesium (High): Normal to Missing	31
Magnesium (High): Grade 1 to Normal	12
Magnesium (High): Grade 1 to 1	7
Magnesium (High): Grade 3 to Normal	2
Magnesium (High): Grade 3 to 3	2
Magnesium (High): Grade 4 to Normal	1
Magnesium (High): Grade 4 to 4	1
Magnesium (High): Missing to Normal	85
Magnesium (High): Missing to Grade 1	12
Magnesium (High): Missing to Grade 3	6
Magnesium (High): Missing to Missing	11
Magnesium (Low): Normal to Normal	857
Magnesium (Low): Normal to Grade 1	319
Magnesium (Low): Normal to Grade 2	28
Magnesium (Low): Normal to Grade 3	9
Magnesium (Low): Normal to Grade 4	3
Magnesium (Low): Normal to Missing	28
Magnesium (Low): Grade 1 to Normal	9
Magnesium (Low): Grade 1 to 1	55
Magnesium (Low): Grade 1 to 2	7
Magnesium (Low): Grade 1 to 3	3
Magnesium (Low): Grade 1 to Missing	3
Magnesium (Low): Grade 4 to 4	1
Magnesium (Low): Missing to Normal	81
Magnesium (Low): Missing to Grade 1	19
Magnesium (Low): Missing to Grade 2	1
Magnesium (Low): Missing to Grade 3	1
Magnesium (Low): Missing to Grade 4	1
Magnesium (Low): Missing to Missing	11
Potassium (High): Normal to Normal	1051
Potassium (High): Normal to Grade 1	183
Potassium (High): Normal to Grade 2	81
Potassium (High): Normal to Grade 3	18
Potassium (High): Normal to Grade 4	8
Potassium (High): Normal to Missing	26
Potassium (High): Grade 1 to Normal	16
Potassium (High): Grade 1 to 1	8
Potassium (High): Grade 1 to 2	7
Potassium (High): Grade 1 to 3	1
Potassium (High): Grade 1 to Missing	3
Potassium (High): Grade 2 to Normal	2
Potassium (High): Grade 2 to 1	1
Potassium (High): Grade 2 to 2	1
Potassium (High): Grade 4 to Normal	1
Potassium (High): Missing to Normal	18
Potassium (High): Missing to Grade 1	5
Potassium (High): Missing to Grade 2	3
Potassium (High): Missing to Missing	3
Potassium (Low): Normal to Normal	990
Potassium (Low): Normal to Grade 2	367
Potassium (Low): Normal to Missing	29
Potassium (Low): Grade 2 to Normal	8
Potassium (Low): Grade 2 to 2	13
Potassium (Low): Missing to Normal	19
Potassium (Low): Missing to Grade 2	7
Potassium (Low): Missing to Missing	3
Sodium (High): Normal to Normal	1075
Sodium (High): Normal to Grade 1	256
Sodium (High): Normal to Grade 2	36
Sodium (High): Normal to Grade 3	9
Sodium (High): Normal to Grade 4	1
Sodium (High): Normal to Missing	28
Sodium (High): Grade 1 to Normal	3
Sodium (High): Grade 1 to 1	6
Sodium (High): Grade 1 to 2	3
Sodium (High): Grade 1 to 3	1
Sodium (High): Grade 2 to 2	2
Sodium (High): Grade 2 to 3	1
Sodium (High): Grade 3 to Normal	1
Sodium (High): Grade 3 to Missing	1
Sodium (High): Missing to Normal	11
Sodium (High): Missing to Grade 1	1
Sodium (High): Missing to Missing	1
Sodium (Low): Normal to Normal	994
Sodium (Low): Normal to Grade 1	298
Sodium (Low): Normal to Grade 3	20
Sodium (Low): Normal to Grade 4	15
Sodium (Low): Normal to Missing	23
Sodium (Low): Grade 1 to Normal	21
Sodium (Low): Grade 1 to 1	36
Sodium (Low): Grade 1 to 3	2
Sodium (Low): Grade 1 to 4	1
Sodium (Low): Grade 1 to Missing	6
Sodium (Low): Grade 3 to Normal	1
Sodium (Low): Grade 3 to 1	2
Sodium (Low): Grade 3 to 3	1
Sodium (Low): Grade 4 to Normal	2
Sodium (Low): Grade 4 to 1	1
Sodium (Low): Missing to Normal	6
Sodium (Low): Missing to Grade 1	5
Sodium (Low): Missing to Grade 3	1
Sodium (Low): Missing to Missing	1
Total Bilirubin: Normal to Normal	1231
Total Bilirubin: Normal to Grade 1	88
Total Bilirubin: Normal to Grade 2	35
Total Bilirubin: Normal to Grade 3	2
Total Bilirubin: Normal to Missing	28
Total Bilirubin: Grade 1 to Normal	3
Total Bilirubin: Grade 1 to 1	11
Total Bilirubin: Grade 1 to 2	6
Total Bilirubin: Grade 1 to Missing	2
Total Bilirubin: Grade 2 to 1	1
Total Bilirubin: Grade 2 to 2	1
Total Bilirubin: Grade 2 to Missing	1
Total Bilirubin: Grade 3 to Normal	1
Total Bilirubin: Missing to Normal	22
Total Bilirubin: Missing to Grade 2	1
Total Bilirubin: Missing to Missing	3
Uric Acid: Normal to Normal	933
Uric Acid: Normal to Grade 1	190
Uric Acid: Normal to Grade 4	8
Uric Acid: Normal to Missing	20
Uric Acid: Grade 1 to Normal	58
Uric Acid: Grade 1 to 1	120
Uric Acid: Grade 1 to 4	6
Uric Acid: Grade 1 to Missing	11
Uric Acid: Grade 4 to Normal	1
Uric Acid: Grade 4 to 1	2
Uric Acid: Grade 4 to 4	4
Uric Acid: Grade 4 to Missing	1
Uric Acid: Missing to Normal	57
Uric Acid: Missing to Grade 1	13
Uric Acid: Missing to Grade 4	2
Uric Acid: Missing to Missing	10

No statistical analyses for this end point

Primary: Number of Participants with Laboratory Abnormalities in Biochemistry Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to Normal Range Criteria

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End point title

Number of Participants with Laboratory Abnormalities in Biochemistry Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to Normal Range Criteria ^[29]

End point description

Clinical laboratory tests for biochemistry parameters were performed at local laboratories. Laboratory toxicities were defined based on local laboratory normal ranges (for parameters with NCI-CTC grade not defined). Some laboratory parameters are bi-dimensional (i.e. can be graded in both the low and high direction). These parameters were split and presented in both directions. Baseline was defined as the last non-missing measurement taken prior to the first dose of study treatment (including unscheduled assessments). Values from all visits, including unscheduled visits, were included in the derivation of the worst post-baseline grade. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: was clinically significant (per investigator); was accompanied by clinical symptoms; resulted in a change in study treatment; or resulted in a medical intervention or a change in concomitant therapy.

End point type

Primary

End point timeframe

Notes
[29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no formal statistical hypothesis tests to be performed. All results were summarized by descriptive statistics.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Participants
Blood Urea Nitrogen (High): Normal to Normal	717
Blood Urea Nitrogen (High): Normal to Low	5
Blood Urea Nitrogen (High): Normal to High	402
Blood Urea Nitrogen (High): Normal to Missing	2
Blood Urea Nitrogen (High): Low to Normal	69
Blood Urea Nitrogen (High): Low to Low	8
Blood Urea Nitrogen (High): Low to High	12
Blood Urea Nitrogen (High): High to Normal	23
Blood Urea Nitrogen (High): High to High	98
Blood Urea Nitrogen (High): Missing to Normal	42
Blood Urea Nitrogen (High): Missing to High	19
Blood Urea Nitrogen (High): Missing to Missing	39
Blood Urea Nitrogen (Low): Normal to Normal	828
Blood Urea Nitrogen (Low): Normal to Low	293
Blood Urea Nitrogen (Low): Normal to High	3
Blood Urea Nitrogen (Low): Normal to Missing	2
Blood Urea Nitrogen (Low): Low to Normal	17
Blood Urea Nitrogen (Low): Low to Low	72
Blood Urea Nitrogen (Low): High to Normal	104
Blood Urea Nitrogen (Low): High to Low	11
Blood Urea Nitrogen (Low): High to High	6
Blood Urea Nitrogen (Low): Missing to Normal	47
Blood Urea Nitrogen (Low): Missing to Low	11
Blood Urea Nitrogen (Low): Missing to High	3
Blood Urea Nitrogen (Low): Missing to Missing	39
Calc Creatinine Clearance (High): Normal to Normal	540
Calc Creatinine Clearance (High): Normal to Low	11
Calc Creatinine Clearance (High): Normal to High	201
Calc Creatinine Clearance(High): Normal to Missing	2
Calc Creatinine Clearance (High): Low to Normal	166
Calc Creatinine Clearance (High): Low to Low	107
Calc Creatinine Clearance (High): Low to High	34
Calc Creatinine Clearance (High): Low to Missing	1
Calc Creatinine Clearance (High): High to Normal	13
Calc Creatinine Clearance (High): High to High	101
Calc Creatinine Clearance(High): Missing to Normal	46
Calc Creatinine Clearance (High): Missing to Low	8
Calc Creatinine Clearance (High): Missing to High	11
Calc Creatinine Clearance(High):Missing to Missing	195
Calc Creatinine Clearance (Low): Normal to Normal	393
Calc Creatinine Clearance (Low): Normal to Low	353
Calc Creatinine Clearance (Low): Normal to High	8
Calc Creatinine Clearance (Low): Low to Normal	12
Calc Creatinine Clearance (Low): Low to Low	294
Calc Creatinine Clearance (Low): Low to High	1
Calc Creatinine Clearance (Low): Low to Missing	1
Calc Creatinine Clearance (Low): High to Normal	61
Calc Creatinine Clearance (Low): High to Low	36
Calc Creatinine Clearance (Low): High to High	17
Calc Creatinine Clearance (Low): Missing to Normal	66
Calc Creatinine Clearance (Low): Missing to Low	44
Calc Creatinine Clearance (Low): Missing to High	17
Calc Creatinine Clearance(Low): Missing to Missing	133
Chloride (High): Normal to Normal	665
Chloride (High): Normal to Low	2
Chloride (High): Normal to High	508
Chloride (High): Low to Normal	54
Chloride (High): Low to High	13
Chloride (High): High to Normal	4
Chloride (High): High to High	58
Chloride (High): Missing to Normal	41
Chloride (High): Missing to High	32
Chloride (High): Missing to Missing	59
Chloride (Low): Normal to Normal	971
Chloride (Low): Normal to Low	201
Chloride (Low): Normal to High	3
Chloride (Low): Low to Normal	31
Chloride (Low): Low to Low	36
Chloride (Low): High to Normal	57
Chloride (Low): High to Low	4
Chloride (Low): High to High	1
Chloride (Low): Missing to Normal	60
Chloride (Low): Missing to Low	13
Chloride (Low): Missing to High	1
Chloride (Low): Missing to Missing	58
Lactate Dehydrogenase (High): Normal to Normal	328
Lactate Dehydrogenase (High): Normal to High	499
Lactate Dehydrogenase (High): Low to Normal	10
Lactate Dehydrogenase (High): Low to Low	1
Lactate Dehydrogenase (High): Low to High	4
Lactate Dehydrogenase (High): High to Normal	74
Lactate Dehydrogenase (High): High to High	449
Lactate Dehydrogenase (High): Missing to Normal	16
Lactate Dehydrogenase (High): Missing to High	30
Lactate Dehydrogenase (High): Missing to Missing	25
Lactate Dehydrogenase (Low): Normal to Normal	716
Lactate Dehydrogenase (Low): Normal to Low	102
Lactate Dehydrogenase (Low): Normal to High	9
Lactate Dehydrogenase (Low): Low to Normal	5
Lactate Dehydrogenase (Low): Low to Low	9
Lactate Dehydrogenase (Low): Low to High	1
Lactate Dehydrogenase (Low): High to Normal	426
Lactate Dehydrogenase (Low): High to Low	31
Lactate Dehydrogenase (Low): High to High	66
Lactate Dehydrogenase (Low): Missing to Normal	39
Lactate Dehydrogenase (Low): Missing to Low	3
Lactate Dehydrogenase (Low): Missing to High	3
Lactate Dehydrogenase (Low): Missing to Missing	26
Total Protein (High): Normal to Normal	1091
Total Protein (High): Normal to Low	20
Total Protein (High): Normal to High	110
Total Protein (High): Low to Normal	72
Total Protein (High): Low to Low	14
Total Protein (High): High to Normal	28
Total Protein (High): High to High	24
Total Protein (High): Missing to Normal	38
Total Protein (High): Missing to Low	3
Total Protein (High): Missing to High	4
Total Protein (High): Missing to Missing	32
Total Protein (Low): Normal to Normal	530
Total Protein (Low): Normal to Low	691
Total Protein (Low): Low to Normal	4
Total Protein (Low): Low to Low	82
Total Protein (Low): High to Normal	41
Total Protein (Low): High to Low	11
Total Protein (Low): Missing to Normal	23
Total Protein (Low): Missing to Low	23
Total Protein (Low): Missing to Missing	31

No statistical analyses for this end point

Secondary: Progression-Free Survival, as Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)

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End point title

Progression-Free Survival, as Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)

End point description

Progression-free survival (PFS) was defined as the time between the date of enrollment and the date of first radiographically documented progressive disease assessment (by the investigator using RECIST v1.1) or death, whichever occurred first. PFS was analyzed using a Kaplan-Meier approach. Participants who had neither progressed nor died at the time of clinical cut-off or who were lost to follow-up were censored at the date of the last evaluable tumor assessment (response assessment with the latest end date); if no post-baseline assessments were available, such participants were censored at Day 1. If a participant missed 2 or more consecutive visits, then they were censored at the last evaluable visit prior to the missed visits. Tumor assessments were performed every 3 cycles (1 cycle is 3 weeks) for up to 36 months and at least every 12 cycles thereafter during treatment, and at least every 36 weeks post-treatment (if progression-free after 36 months), until disease progression.

End point type

Secondary

End point timeframe

From date of enrollment until date of disease progression or death, whichever occurred first. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Months
median (confidence interval 95%)	20.67 (18.89 to 23.13)

No statistical analyses for this end point

Secondary: Subgroup Analysis by Region of Enrollment: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

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End point title

Subgroup Analysis by Region of Enrollment: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

End point description

End point type

Secondary

End point timeframe

From date of enrollment until date of disease progression or death, whichever occurred first. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Europe	Asia	North America	South America	Africa	Other (Australia)
Number of subjects analysed	1009	177	34	121	71	24 ^[30]
Units: Months
median (confidence interval 95%)	19.38 (17.51 to 21.75)	23.79 (15.90 to 28.85)	25.17 (14.42 to 29.44)	22.37 (17.51 to 32.72)	22.83 (12.02 to 27.86)	999999 (15.74 to 999999)

Notes
[30] - '999999' means the median and 95% CI could not be calculated because not enough events had occurred.

No statistical analyses for this end point

Secondary: Subgroup Analysis by Age (≤65 vs. >65 Years): Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

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End point title

Subgroup Analysis by Age (≤65 vs. >65 Years): Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

End point description

End point type

Secondary

End point timeframe

From date of enrollment until date of disease progression or death, whichever occurred first. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Age ≤65 Years	Age >65 Years
Number of subjects analysed	1167	269
Units: Months
median (confidence interval 95%)	21.98 (19.65 to 24.25)	14.72 (12.22 to 19.55)

No statistical analyses for this end point

Secondary: Subgroup Analysis by ECOG Performance Status at Baseline: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

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End point title

Subgroup Analysis by ECOG Performance Status at Baseline: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

End point description

End point type

Secondary

End point timeframe

From date of enrollment until date of disease progression or death, whichever occurred first. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	ECOG Performance Status 0 or 1	ECOG Performance Status 2
Number of subjects analysed	1371	63
Units: Months
median (confidence interval 95%)	21.49 (19.45 to 23.98)	12.88 (8.67 to 15.90)

No statistical analyses for this end point

Secondary: Subgroup Analysis by Taxane Chemotherapy: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

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End point title

Subgroup Analysis by Taxane Chemotherapy: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

End point description

End point type

Secondary

End point timeframe

From date of enrollment until date of disease progression or death, whichever occurred first. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Docetaxel	Paclitaxel	Nab-Paclitaxel
Number of subjects analysed	775	588	65
Units: Months
median (confidence interval 95%)	19.38 (16.92 to 22.11)	23.23 (19.58 to 25.59)	19.22 (11.70 to 37.09)

No statistical analyses for this end point

Secondary: Subgroup Analysis by Visceral Disease at Baseline: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

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End point title

Subgroup Analysis by Visceral Disease at Baseline: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

End point description

End point type

Secondary

End point timeframe

From date of enrollment until date of disease progression or death, whichever occurred first. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Visceral Disease	Non-Visceral Disease
Number of subjects analysed	992	444
Units: Months
median (confidence interval 95%)	18.23 (16.13 to 20.57)	27.24 (23.75 to 34.40)

No statistical analyses for this end point

Secondary: Subgroup Analysis by Prior (Neo)Adjuvant Chemotherapy: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

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End point title

Subgroup Analysis by Prior (Neo)Adjuvant Chemotherapy: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

End point description

End point type

Secondary

End point timeframe

From date of enrollment until date of disease progression or death, whichever occurred first. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Prior (Neo)Adjuvant Chemotherapy	No Prior (Neo)Adjuvant Chemotherapy
Number of subjects analysed	786	650
Units: Months
median (confidence interval 95%)	19.12 (16.59 to 21.49)	23.49 (20.57 to 25.63)

No statistical analyses for this end point

Secondary: Subgroup Analysis by Hormone Receptor Status at Baseline: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

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End point title

Subgroup Analysis by Hormone Receptor Status at Baseline: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

End point description

End point type

Secondary

End point timeframe

From date of enrollment until date of disease progression or death, whichever occurred first. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Hormone Receptor Positive	Hormone Receptor Negative	Hormone Receptor Status Unknown
Number of subjects analysed	918	512	6
Units: Months
median (confidence interval 95%)	20.60 (18.53 to 23.82)	20.73 (17.05 to 23.79)	32.13 (11.63 to 61.57)

No statistical analyses for this end point

Secondary: Subgroup Analysis by Previous Trastuzumab Therapy: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

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End point title

Subgroup Analysis by Previous Trastuzumab Therapy: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

End point description

End point type

Secondary

End point timeframe

From date of enrollment until date of disease progression or death, whichever occurred first. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Previous Trastuzumab Therapy	No Previous Trastuzumab Therapy
Number of subjects analysed	400	1036
Units: Months
median (confidence interval 95%)	15.38 (13.67 to 19.02)	23.39 (20.67 to 25.00)

No statistical analyses for this end point

Secondary: Overall Survival

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End point title

Overall Survival

End point description

Overall survival was defined as time from the date of enrollment until the date of death due to any cause. Overall survival was analyzed using a Kaplan-Meier approach. Participants who had not died were censored at the last date they were known to be alive. When it was not possible to confirm the full death date, partial death dates were imputed to: 01 June of that year if only the year was known, 15th of that month if only the month and year were known. If the imputed date was before the last known alive date, the last known alive date was used as the imputation.

End point type

Secondary

End point timeframe

From date of enrollment until death due to any cause. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1436
Units: Months
median (confidence interval 95%)	65.31 (60.88 to 70.87)

No statistical analyses for this end point

Secondary: Subgroup Analysis by Region of Enrollment: Overall Survival

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End point title

Subgroup Analysis by Region of Enrollment: Overall Survival

End point description

End point type

Secondary

End point timeframe

From date of enrollment until death due to any cause. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Europe	Asia	North America	South America	Africa	Other (Australia)
Number of subjects analysed	1009	177 ^[31]	34 ^[32]	121 ^[33]	71	24 ^[34]
Units: Months
median (confidence interval 95%)	66.56 (61.90 to 73.49)	63.57 (47.57 to 999999)	55.56 (41.49 to 999999)	999999 (49.84 to 999999)	53.22 (33.35 to 63.87)	999999 (44.16 to 999999)

Notes
[31] - '999999' means the 95% CI could not be calculated because not enough events had occurred.
[32] - '999999' means the 95% CI could not be calculated because not enough events had occurred.
[33] - '999999' means the median and 95% CI could not be calculated because not enough events had occurred.
[34] - '999999' means the median and 95% CI could not be calculated because not enough events had occurred.

No statistical analyses for this end point

Secondary: Subgroup Analysis by Age (≤65 vs. >65 Years): Overall Survival

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End point title

Subgroup Analysis by Age (≤65 vs. >65 Years): Overall Survival

End point description

End point type

Secondary

End point timeframe

From date of enrollment until death due to any cause. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Age ≤65 Years	Age >65 Years
Number of subjects analysed	1167	269
Units: Months
median (confidence interval 95%)	70.01 (64.33 to 81.08)	50.10 (41.26 to 53.98)

No statistical analyses for this end point

Secondary: Subgroup Analysis by ECOG Performance Status at Baseline: Overall Survival

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End point title

Subgroup Analysis by ECOG Performance Status at Baseline: Overall Survival

End point description

End point type

Secondary

End point timeframe

From date of enrollment until death due to any cause. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	ECOG Performance Status 0 or 1	ECOG Performance Status 2
Number of subjects analysed	1371	63
Units: Months
median (confidence interval 95%)	67.25 (63.44 to 76.52)	31.15 (20.50 to 39.13)

No statistical analyses for this end point

Secondary: Subgroup Analysis by Taxane Chemotherapy: Overall Survival

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End point title

Subgroup Analysis by Taxane Chemotherapy: Overall Survival

End point description

End point type

Secondary

End point timeframe

From date of enrollment until death due to any cause. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Docetaxel	Paclitaxel	Nab-Paclitaxel
Number of subjects analysed	775	588	65 ^[35]
Units: Months
median (confidence interval 95%)	66.53 (61.67 to 77.27)	64.03 (56.61 to 72.25)	70.87 (39.69 to 999999)

Notes
[35] - '999999' means the 95% CI could not be calculated because not enough events had occurred.

No statistical analyses for this end point

Secondary: Subgroup Analysis by Visceral Disease at Baseline: Overall Survival

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End point title

Subgroup Analysis by Visceral Disease at Baseline: Overall Survival

End point description

End point type

Secondary

End point timeframe

From date of enrollment until death due to any cause. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Visceral Disease	Non-Visceral Disease
Number of subjects analysed	992	444 ^[36]
Units: Months
median (confidence interval 95%)	57.10 (52.40 to 63.44)	81.08 (71.66 to 999999)

Notes
[36] - '999999' means the 95% CI could not be calculated because not enough events had occurred.

No statistical analyses for this end point

Secondary: Subgroup Analysis by Prior (Neo)Adjuvant Chemotherapy: Overall Survival

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End point title

Subgroup Analysis by Prior (Neo)Adjuvant Chemotherapy: Overall Survival

End point description

End point type

Secondary

End point timeframe

From date of enrollment until death due to any cause. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Prior (Neo)Adjuvant Chemotherapy	No Prior (Neo)Adjuvant Chemotherapy
Number of subjects analysed	786	650 ^[37]
Units: Months
median (confidence interval 95%)	57.10 (51.06 to 62.82)	79.80 (71.79 to 999999)

Notes
[37] - '999999' means the 95% CI could not be calculated because not enough events had occurred.

No statistical analyses for this end point

Secondary: Subgroup Analysis by Hormone Receptor Status at Baseline: Overall Survival

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End point title

Subgroup Analysis by Hormone Receptor Status at Baseline: Overall Survival

End point description

End point type

Secondary

End point timeframe

From date of enrollment until death due to any cause. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Hormone Receptor Positive	Hormone Receptor Negative	Hormone Receptor Status Unknown
Number of subjects analysed	918	512	6 ^[38]
Units: Months
median (confidence interval 95%)	66.66 (62.39 to 77.27)	60.19 (52.34 to 67.71)	999999 (16.13 to 999999)

Notes
[38] - '999999' means the median and 95% CI could not be calculated because not enough events had occurred.

No statistical analyses for this end point

Secondary: Subgroup Analysis by Previous Trastuzumab Therapy: Overall Survival

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End point title

Subgroup Analysis by Previous Trastuzumab Therapy: Overall Survival

End point description

End point type

Secondary

End point timeframe

From date of enrollment until death due to any cause. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Previous Trastuzumab Therapy	No Previous Trastuzumab Therapy
Number of subjects analysed	400	1036 ^[39]
Units: Months
median (confidence interval 95%)	54.08 (48.66 to 60.75)	73.50 (65.61 to 999999)

Notes
[39] - '999999' means the 95% CI could not be calculated because not enough events had occurred.

No statistical analyses for this end point

Secondary: Overall Response Rate (Complete Response or Partial Response) Based on Best Overall Response (Confirmed) as Assessed by the Investigator Using RECIST v1.1

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End point title

Overall Response Rate (Complete Response or Partial Response) Based on Best Overall Response (Confirmed) as Assessed by the Investigator Using RECIST v1.1

End point description

The overall response rate was defined as the percentage of participants with complete response (CR) or partial response (PR) as their best confirmed response (≥4 weeks later), as assessed by the investigator using RECIST v1.1 from the start of study treatment until disease progression/recurrence or death. Responses according to RECIST v1.1 are defined as follows: CR = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimetres (mm).; PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants without post-baseline tumor assessments were considered non-responders.

End point type

Secondary

End point timeframe

Assessed every 3 cycles (1 cycle is 3 weeks) up to 36 months, and at least every 12 cycles thereafter, until disease progression or death. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1198
Units: Percentage of participants
number (confidence interval 95%)	79.5 (77.07 to 81.72)

No statistical analyses for this end point

Secondary: Percentage of Participants by Best Overall Response as Assessed by the Investigator Using RECIST v1.1

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End point title

Percentage of Participants by Best Overall Response as Assessed by the Investigator Using RECIST v1.1

End point description

Best overall response (BOR) was defined as the best response recorded from the first dose of study treatment until disease progression/recurrence or death in the absence of disease progression. The hierarchy used to determine BOR: Complete Response (CR)>Partial Response (PR)>Stable Disease (SD)>Progressive Disease (PD)>Not Evaluable. Note that CR or PR was confirmed ≥4 weeks later. RECIST v1.1 responses are defined as follows: CR = Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must have reduction in short axis to <10 millimetres (mm).; PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum.; PD = At least 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study, and absolute increase of ≥5 mm.; SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

End point type

Secondary

End point timeframe

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1198 ^[40]
Units: Percentage of participants
number (not applicable)
Complete Response (Confirmed)	14.6
Partial Response (Confirmed)	64.9
Stable Disease	15.3
Progressive Disease	4.2
Not Evaluable	1.1

Notes
[40] - Only includes subjects with measurable disease at baseline.

No statistical analyses for this end point

Secondary: Subgroup Analysis by Age (≤65 vs. >65 Years): Overall Response Rate (Complete Response or Partial Response) Based on Best Overall Response (Confirmed) as Assessed by the Investigator Using RECIST v1.1

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End point title

Subgroup Analysis by Age (≤65 vs. >65 Years): Overall Response Rate (Complete Response or Partial Response) Based on Best Overall Response (Confirmed) as Assessed by the Investigator Using RECIST v1.1

End point description

End point type

Secondary

End point timeframe

End point values	Age ≤65 Years	Age >65 Years
Number of subjects analysed	968 ^[41]	230 ^[42]
Units: Percentage of participants
number (confidence interval 95%)	81.7 (79.13 to 84.10)	70.0 (63.63 to 75.85)

Notes
[41] - Only includes subjects with measurable disease at baseline.
[42] - Only includes subjects with measurable disease at baseline.

No statistical analyses for this end point

Secondary: Subgroup Analysis by Taxane Chemotherapy: Overall Response Rate (Complete Response or Partial Response) Based on Best Overall Response (Confirmed) as Assessed by the Investigator Using RECIST v1.1

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End point title

Subgroup Analysis by Taxane Chemotherapy: Overall Response Rate (Complete Response or Partial Response) Based on Best Overall Response (Confirmed) as Assessed by the Investigator Using RECIST v1.1

End point description

End point type

Secondary

End point timeframe

End point values	Docetaxel	Paclitaxel	Nab-Paclitaxel
Number of subjects analysed	657 ^[43]	481 ^[44]	53 ^[45]
Units: Percentage of participants
number (confidence interval 95%)	78.4 (75.04 to 81.48)	82.1 (78.40 to 85.44)	77.4 (63.79 to 87.72)

Notes
[43] - Only includes subjects with measurable disease at baseline and those who had received any taxane.
[44] - Only includes subjects with measurable disease at baseline and those who had received any taxane.
[45] - Only includes subjects with measurable disease at baseline and those who had received any taxane.

No statistical analyses for this end point

Secondary: Clinical Benefit Rate (CR or PR, or SD for at Least 6 Months) Based on Best Overall Response as Assessed by the Investigator Using RECIST v.1.1

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End point title

Clinical Benefit Rate (CR or PR, or SD for at Least 6 Months) Based on Best Overall Response as Assessed by the Investigator Using RECIST v.1.1

End point description

The clinical benefit rate was defined as the percentage of participants whose best confirmed response (≥4 weeks later) was a complete response (CR) or partial response (PR), or stable disease (SD) that lasted at least 6 months, as assessed by the investigator using RECIST v1.1 from the start of study treatment until disease progression/recurrence or death. Clinical benefit responses according to RECIST v1.1 are defined as follows: CR = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimetres (mm).; PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.; SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least 20% increase in sum of diameters of target lesions and absolute increase of ≥5 mm), taking as reference the smallest sum diameters while on study.

End point type

Secondary

End point timeframe

Assessed every 3 cycles (1 cycle is 3 weeks) up to 36 months, and at least every 12 cycles thereafter, until disease progression. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1198 ^[46]
Units: Percentage of participants
number (confidence interval 95%)	86.2 (84.14 to 88.13)

Notes
[46] - Only includes subjects with measurable disease at baseline.

No statistical analyses for this end point

Secondary: Duration of Response as Assessed by the Investigator Using RECIST v1.1

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End point title

Duration of Response as Assessed by the Investigator Using RECIST v1.1

End point description

Duration of response (DOR) was defined as the time from when a confirmed best overall response of complete response (CR) or partial response (PR) was first documented to first documented disease progression or death from any cause (whichever occurred first). DOR was analyzed using a Kaplan-Meier approach. Participants who had not progressed or died after having had a confirmed response were censored at the date of their last tumor measurement. Response was assessed every 3 cycles (1 cycle is 3 weeks) up to 36 months, and at least every 12 cycles thereafter until event occurrence or end of study. Responses according to RECIST v1.1 are defined as follows: CR = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimetres (mm).; PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

End point type

Secondary

End point timeframe

From date of first confirmed response (CR or PR) to first documented disease progression or death from any cause, whichever occurred first. The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	952 ^[47]
Units: Months
median (confidence interval 95%)	20.01 (18.20 to 22.21)

Notes
[47] - Only includes subjects with measurable disease at baseline and a documented confirmed response.

No statistical analyses for this end point

Secondary: Time to Response for Participants with Best Overall Response of Complete Response or Partial Response, as Assessed by the Investigator Using RECIST v1.1

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End point title

Time to Response for Participants with Best Overall Response of Complete Response or Partial Response, as Assessed by the Investigator Using RECIST v1.1

End point description

Time to response (TTR) was defined as the time from the first study treatment administration to the date of first confirmed response (CR or PR). TTR was analyzed using a Kaplan-Meier approach. Participants who did not have CR or PR were censored at the date of their last evaluable tumor assessment. Participants for whom no post-baseline tumor assessments were available were censored at Day 1. Responses according to RECIST v1.1 are defined as follows: CR = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimetres (mm).; PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

End point type

Secondary

End point timeframe

From date of first study treatment until date of first confirmed response (CR or PR). The median (full range) duration of follow-up was 68.73 (0.03-87.29) months.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1198
Units: Months
median (confidence interval 95%)	2.464 (2.398 to 2.497)

No statistical analyses for this end point

Secondary: Change from Baseline in Functional Assessment of Cancer Therapy - Breast Cancer (FACT-B) Questionnaire Total Score Over the Course of the Study

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End point title

Change from Baseline in Functional Assessment of Cancer Therapy - Breast Cancer (FACT-B) Questionnaire Total Score Over the Course of the Study

End point description

The FACT-B questionnaire (version 4) was administered only to female participants to assess quality of life in five subscales: physical, social, emotional, and functional well-being, and breast cancer. Participants were given a series of statements in each subscale and were asked to rate how true each statement was for them during the past 7 days on a 5-point scale ranging from 0 (not at all) to 4 (very much). The calculated FACT-B total score, ranging from 0 to 148, was the sum of the scores for each subscale, provided that at least 80% of the items had been answered; a higher score indicated a better quality of life. If any of the 5 subscale scores were missing, the total score was also set to missing. Baseline was defined as the last non-missing measurement taken prior to first dose of study treatment (including unscheduled assessments). Post-baseline values were summarized for planned visits only.

End point type

Secondary

End point timeframe

Baseline, every 3 cycles (1 cycle is 3 weeks) during treatment period, and 28 days post-treatment safety follow-up. The median (full range) duration of exposure to any study treatment was 16.2 (0.0-86.4) months.

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1429
Units: Score on a scale
arithmetic mean (standard deviation)
Baseline (BL): Absolute Value at Visit (n = 1306)	99.87 ± 20.548
Change from BL at Cycle 3 (n = 1158)	0.40 ± 15.526
Change from BL at Cycle 6 (n = 1089)	-1.93 ± 17.611
Change from BL at Cycle 9 (n = 1006)	0.87 ± 17.211
Change from BL at Cycle 12 (n = 891)	3.03 ± 17.426
Change from BL at Cycle 15 (n = 794)	3.33 ± 18.764
Change from BL at Cycle 18 (n = 718)	3.80 ± 18.689
Change from BL at Cycle 21 (n = 615)	4.06 ± 18.175
Change from BL at Cycle 24 (n = 570)	3.59 ± 19.570
Change from BL at Cycle 27 (n = 512)	3.14 ± 20.311
Change from BL at Cycle 30 (n = 515)	3.75 ± 18.877
Change from BL at Cycle 33 (n = 468)	3.58 ± 20.586
Change from BL at Cycle 36 (n = 427)	3.16 ± 18.838
Change from BL at Cycle 39 (n = 419)	1.66 ± 19.791
Change from BL at Cycle 42 (n = 385)	2.08 ± 20.658
Change from BL at Cycle 45 (n = 361)	2.22 ± 20.811
Change from BL at Cycle 48 (n = 340)	1.51 ± 21.268
Change from BL at Cycle 51 (n = 308)	1.95 ± 20.221
Change from BL at Cycle 54 (n = 282)	0.52 ± 20.784
Change from BL at Cycle 57 (n = 286)	0.54 ± 20.014
Change from BL at Cycle 60 (n = 262)	0.20 ± 21.207
Change from BL at Cycle 63 (n = 268)	0.61 ± 21.475
Change from BL at Cycle 66 (n = 241)	0.44 ± 20.633
Change from BL at Cycle 69 (n = 236)	-0.75 ± 21.419
Change from BL at Cycle 72 (n = 219)	-1.16 ± 21.951
Change from BL at Cycle 75 (n = 213)	-1.14 ± 21.132
Change from BL at Cycle 78 (n = 207)	0.11 ± 20.807
Change from BL at Cycle 81 (n = 192)	-1.03 ± 20.526
Change from BL at Cycle 84 (n = 181)	-1.67 ± 21.030
Change from BL at Cycle 87 (n = 174)	0.62 ± 21.183
Change from BL at Cycle 90 (n = 147)	0.00 ± 22.289
Change from BL at Cycle 93 (n = 129)	0.99 ± 21.474
Change from BL at Cycle 96 (n = 106)	2.36 ± 21.636
Change from BL at Cycle 99 (n = 85)	1.36 ± 23.195
Change from BL at Cycle 102 (n = 69)	1.20 ± 21.262
Change from BL at Cycle 105 (n = 55)	3.13 ± 20.385
Change from BL at Cycle 108 (n = 44)	2.22 ± 23.617
Change from BL at Cycle 111 (n = 36)	-0.48 ± 22.585
Change from BL at Cycle 114 (n = 19)	-4.42 ± 22.323
Change from BL at Cycle 117 (n = 11)	-4.96 ± 16.232
Change from BL at Cycle 120 (n = 4)	-8.64 ± 13.187
Change from BL at Cycle 123 (n = 2)	-20.94 ± 2.357
Change from BL at End of Treatment (n = 454)	-1.06 ± 19.923
Change from BL at Day 28 of Follow-Up (n = 568)	-1.96 ± 21.201

No statistical analyses for this end point

Secondary: Change from Baseline in FACT-B Questionnaire Physical Well-Being Subscale Score Over the Course of the Study

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End point title

Change from Baseline in FACT-B Questionnaire Physical Well-Being Subscale Score Over the Course of the Study

End point description

The FACT-B questionnaire (version 4) was administered only to female participants to assess quality of life in five subscales: physical, social, emotional, and functional well-being, and breast cancer. For the physical well-being subscale, participants were given a series of 7 statements and were asked to rate how true each statement was for them during the past 7 days on a 5-point scale ranging from 0 (not at all) to 4 (very much). The calculated FACT-B physical well-being subscale score, ranging from 0 to 28, was the sum of the scores for each statement only if at least 50% of items had been answered; the higher the score, the better the quality of life. Baseline was defined as the last non-missing measurement taken prior to first dose of study treatment (including unscheduled assessments). Post-baseline values were summarized for planned visits only.

End point type

Secondary

End point timeframe

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1429
Units: Score on a scale
arithmetic mean (standard deviation)
Baseline (BL): Absolute Value at Visit (n = 1331)	20.98 ± 6.044
Change from BL at Cycle 3 (n = 1193)	-1.13 ± 5.557
Change from BL at Cycle 6 (n = 1127)	-1.61 ± 5.994
Change from BL at Cycle 9 (n = 1033)	-0.31 ± 5.604
Change from BL at Cycle 12 (n = 919)	0.51 ± 5.599
Change from BL at Cycle 15 (n = 816)	0.51 ± 5.652
Change from BL at Cycle 18 (n = 734)	0.69 ± 5.543
Change from BL at Cycle 21 (n = 631)	0.73 ± 5.616
Change from BL at Cycle 24 (n = 581)	0.61 ± 5.690
Change from BL at Cycle 27 (n = 526)	0.47 ± 5.761
Change from BL at Cycle 30 (n = 523)	0.71 ± 5.584
Change from BL at Cycle 33 (n = 483)	0.56 ± 5.894
Change from BL at Cycle 36 (n = 437)	0.39 ± 5.512
Change from BL at Cycle 39 (n = 429)	-0.04 ± 5.647
Change from BL at Cycle 42 (n = 396)	0.22 ± 5.604
Change from BL at Cycle 45 (n = 370)	0.09 ± 5.698
Change from BL at Cycle 48 (n = 346)	0.11 ± 5.564
Change from BL at Cycle 51 (n = 319)	0.22 ± 5.280
Change from BL at Cycle 54 (n = 292)	-0.26 ± 5.765
Change from BL at Cycle 57 (n = 296)	-0.35 ± 5.695
Change from BL at Cycle 60 (n = 269)	-0.10 ± 5.630
Change from BL at Cycle 63 (n = 275)	-0.20 ± 5.696
Change from BL at Cycle 66 (n = 246)	0.29 ± 5.338
Change from BL at Cycle 69 (n = 243)	-0.60 ± 5.579
Change from BL at Cycle 72 (n = 224)	-0.35 ± 5.494
Change from BL at Cycle 75 (n = 218)	-0.72 ± 5.507
Change from BL at Cycle 78 (n = 213)	-0.44 ± 5.379
Change from BL at Cycle 81 (n = 197)	-0.65 ± 5.029
Change from BL at Cycle 84 (n = 186)	-0.81 ± 5.249
Change from BL at Cycle 87 (n = 181)	-0.36 ± 5.391
Change from BL at Cycle 90 (n = 153)	-0.66 ± 5.332
Change from BL at Cycle 93 (n = 134)	-0.42 ± 5.788
Change from BL at Cycle 96 (n = 110)	-0.28 ± 5.178
Change from BL at Cycle 99 (n = 88)	-0.21 ± 5.474
Change from BL at Cycle 102 (n = 72)	-0.80 ± 5.269
Change from BL at Cycle 105 (n = 57)	-0.07 ± 5.133
Change from BL at Cycle 108 (n = 45)	0.07 ± 5.775
Change from BL at Cycle 111 (n = 37)	0.38 ± 5.309
Change from BL at Cycle 114 (n = 20)	-1.70 ± 4.950
Change from BL at Cycle 117 (n = 12)	-1.83 ± 3.474
Change from BL at Cycle 120 (n = 4)	-2.38 ± 3.092
Change from BL at Cycle 123 (n = 2)	-5.58 ± 2.946
Change from BL at End of Treatment (n = 465)	-0.73 ± 6.366
Change from BL at Day 28 of Follow-Up (n = 583)	-0.95 ± 6.393

No statistical analyses for this end point

Secondary: Change from Baseline in FACT-B Questionnaire Social Well-Being Subscale Score Over the Course of the Study

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End point title

Change from Baseline in FACT-B Questionnaire Social Well-Being Subscale Score Over the Course of the Study

End point description

The FACT-B questionnaire (version 4) was administered only to female participants to assess quality of life in five subscales: physical, social, emotional, and functional well-being, and breast cancer. For the social well-being subscale, participants were given a series of 7 statements and were asked to rate how true each statement was for them during the past 7 days on a 5-point scale ranging from 0 (not at all) to 4 (very much). The calculated FACT-B social well-being subscale score, ranging from 0 to 28, was the sum of the scores for each statement only if at least 50% of items had been answered; the higher the score, the better the quality of life. Baseline was defined as the last non-missing measurement taken prior to first dose of study treatment (including unscheduled assessments). Post-baseline values were summarized for planned visits only.

End point type

Secondary

End point timeframe

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1429
Units: Score on a scale
arithmetic mean (standard deviation)
Baseline (BL): Absolute Value at Visit (n = 1329)	22.24 ± 4.993
Change from BL at Cycle 3 (n = 1189)	-0.41 ± 4.145
Change from BL at Cycle 6 (n = 1118)	-1.09 ± 4.320
Change from BL at Cycle 9 (n = 1032)	-1.02 ± 4.728
Change from BL at Cycle 12 (n = 921)	-1.19 ± 4.846
Change from BL at Cycle 15 (n = 812)	-1.28 ± 4.949
Change from BL at Cycle 18 (n = 733)	-1.19 ± 4.986
Change from BL at Cycle 21 (n = 630)	-1.24 ± 4.881
Change from BL at Cycle 24 (n = 580)	-1.26 ± 4.856
Change from BL at Cycle 27 (n = 525)	-1.48 ± 4.994
Change from BL at Cycle 30 (n = 523)	-1.18 ± 5.107
Change from BL at Cycle 33 (n = 482)	-1.45 ± 4.852
Change from BL at Cycle 36 (n = 437)	-1.54 ± 4.953
Change from BL at Cycle 39 (n = 430)	-1.77 ± 5.066
Change from BL at Cycle 42 (n = 394)	-1.73 ± 5.154
Change from BL at Cycle 45 (n = 370)	-1.50 ± 5.238
Change from BL at Cycle 48 (n = 345)	-1.84 ± 5.475
Change from BL at Cycle 51 (n = 318)	-2.01 ± 5.657
Change from BL at Cycle 54 (n = 293)	-1.77 ± 5.236
Change from BL at Cycle 57 (n = 297)	-1.88 ± 5.117
Change from BL at Cycle 60 (n = 270)	-2.01 ± 5.528
Change from BL at Cycle 63 (n = 277)	-2.18 ± 5.278
Change from BL at Cycle 66 (n = 246)	-2.19 ± 5.586
Change from BL at Cycle 69 (n = 243)	-2.24 ± 5.434
Change from BL at Cycle 72 (n = 224)	-2.49 ± 5.846
Change from BL at Cycle 75 (n = 219)	-2.40 ± 5.777
Change from BL at Cycle 78 (n = 213)	-2.33 ± 5.676
Change from BL at Cycle 81 (n = 197)	-2.53 ± 5.609
Change from BL at Cycle 84 (n = 187)	-2.96 ± 5.624
Change from BL at Cycle 87 (n = 181)	-2.29 ± 5.487
Change from BL at Cycle 90 (n = 152)	-2.38 ± 5.355
Change from BL at Cycle 93 (n = 134)	-1.97 ± 5.102
Change from BL at Cycle 96 (n = 110)	-1.94 ± 4.831
Change from BL at Cycle 99 (n = 89)	-2.07 ± 5.316
Change from BL at Cycle 102 (n = 73)	-1.70 ± 4.258
Change from BL at Cycle 105 (n = 58)	-1.76 ± 4.074
Change from BL at Cycle 108 (n = 46)	-1.75 ± 3.387
Change from BL at Cycle 111 (n = 38)	-1.94 ± 3.663
Change from BL at Cycle 114 (n = 20)	-2.31 ± 3.386
Change from BL at Cycle 117 (n = 12)	-1.83 ± 3.600
Change from BL at Cycle 120 (n = 4)	-2.85 ± 5.485
Change from BL at Cycle 123 (n = 2)	-1.92 ± 2.946
Change from BL at End of Treatment (n = 461)	-1.29 ± 4.911
Change from BL at Day 28 of Follow-Up (n = 581)	-1.61 ± 5.080

No statistical analyses for this end point

Secondary: Change from Baseline in FACT-B Questionnaire Emotional Well-Being Subscale Score Over the Course of the Study

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End point title

Change from Baseline in FACT-B Questionnaire Emotional Well-Being Subscale Score Over the Course of the Study

End point description

The FACT-B questionnaire (version 4) was administered only to female participants to assess quality of life in five subscales: physical, social, emotional, and functional well-being, and breast cancer. For the emotional well-being subscale, participants were given a series of 6 statements and were asked to rate how true each statement was for them during the past 7 days on a 5-point scale ranging from 0 (not at all) to 4 (very much). The calculated FACT-B emotional well-being subscale score, ranging from 0 to 24, was the sum of the scores for each statement only if at least 50% of items had been answered; the higher the score, the better the quality of life. Baseline was defined as the last non-missing measurement taken prior to first dose of study treatment (including unscheduled assessments). Post-baseline values were summarized for planned visits only.

End point type

Secondary

End point timeframe

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1429
Units: Score on a scale
arithmetic mean (standard deviation)
Baseline (BL): Absolute Value at Visit (n = 1333)	15.08 ± 4.990
Change from BL at Cycle 3 (n = 1194)	1.69 ± 4.219
Change from BL at Cycle 6 (n = 1124)	1.53 ± 4.526
Change from BL at Cycle 9 (n = 1032)	1.64 ± 4.624
Change from BL at Cycle 12 (n = 916)	2.02 ± 4.686
Change from BL at Cycle 15 (n = 811)	1.98 ± 4.778
Change from BL at Cycle 18 (n = 731)	2.03 ± 4.861
Change from BL at Cycle 21 (n = 628)	2.17 ± 4.877
Change from BL at Cycle 24 (n = 581)	2.19 ± 5.040
Change from BL at Cycle 27 (n = 523)	2.21 ± 5.171
Change from BL at Cycle 30 (n = 523)	2.17 ± 4.763
Change from BL at Cycle 33 (n = 478)	2.21 ± 5.275
Change from BL at Cycle 36 (n = 435)	2.32 ± 5.130
Change from BL at Cycle 39 (n = 430)	1.99 ± 5.115
Change from BL at Cycle 42 (n = 394)	1.96 ± 5.451
Change from BL at Cycle 45 (n = 367)	2.25 ± 5.367
Change from BL at Cycle 48 (n = 343)	1.82 ± 5.414
Change from BL at Cycle 51 (n = 317)	2.32 ± 5.311
Change from BL at Cycle 54 (n = 288)	1.84 ± 5.325
Change from BL at Cycle 57 (n = 293)	1.80 ± 5.256
Change from BL at Cycle 60 (n = 268)	1.59 ± 5.462
Change from BL at Cycle 63 (n = 274)	1.70 ± 5.336
Change from BL at Cycle 66 (n = 246)	1.52 ± 5.074
Change from BL at Cycle 69 (n = 243)	1.83 ± 5.351
Change from BL at Cycle 72 (n = 223)	1.56 ± 5.421
Change from BL at Cycle 75 (n = 217)	1.58 ± 5.308
Change from BL at Cycle 78 (n = 210)	1.72 ± 5.463
Change from BL at Cycle 81 (n = 196)	2.01 ± 5.750
Change from BL at Cycle 84 (n = 185)	2.06 ± 5.384
Change from BL at Cycle 87 (n = 180)	1.97 ± 5.558
Change from BL at Cycle 90 (n = 151)	2.08 ± 5.686
Change from BL at Cycle 93 (n = 134)	2.17 ± 5.388
Change from BL at Cycle 96 (n = 109)	2.40 ± 5.769
Change from BL at Cycle 99 (n = 88)	2.30 ± 6.041
Change from BL at Cycle 102 (n = 71)	2.07 ± 5.949
Change from BL at Cycle 105 (n = 58)	2.58 ± 5.902
Change from BL at Cycle 108 (n = 46)	2.34 ± 6.721
Change from BL at Cycle 111 (n = 38)	1.19 ± 7.241
Change from BL at Cycle 114 (n = 20)	1.55 ± 7.944
Change from BL at Cycle 117 (n = 12)	1.33 ± 4.185
Change from BL at Cycle 120 (n = 4)	0.75 ± 2.217
Change from BL at Cycle 123 (n = 2)	-0.50 ± 2.121
Change from BL at End of Treatment (n = 465)	0.30 ± 5.001
Change from BL at Day 28 of Follow-Up (n = 585)	0.37 ± 5.193

No statistical analyses for this end point

Secondary: Change from Baseline in FACT-B Questionnaire Functional Well-Being Subscale Score Over the Course of the Study

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End point title

Change from Baseline in FACT-B Questionnaire Functional Well-Being Subscale Score Over the Course of the Study

End point description

The FACT-B questionnaire (version 4) was administered only to female participants to assess quality of life in five subscales: physical, social, emotional, and functional well-being, and breast cancer. For the functional well-being subscale, participants were given a series of 7 statements and were asked to rate how true each statement was for them during the past 7 days on a 5-point scale ranging from 0 (not at all) to 4 (very much). The calculated FACT-B functional well-being subscale score, ranging from 0 to 28, was the sum of the scores for each statement only if at least 50% of items had been answered; the higher the score, the better the quality of life. Baseline was defined as the last non-missing measurement taken prior to first dose of study treatment (including unscheduled assessments). Post-baseline values were summarized for planned visits only.

End point type

Secondary

End point timeframe

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1429
Units: Score on a scale
arithmetic mean (standard deviation)
Baseline (BL): Absolute Value at Visit (n = 1335)	16.65 ± 6.096
Change from BL at Cycle 3 (n = 1192)	-0.47 ± 4.961
Change from BL at Cycle 6 (n = 1125)	-0.79 ± 5.437
Change from BL at Cycle 9 (n = 1032)	-0.11 ± 5.572
Change from BL at Cycle 12 (n = 915)	0.46 ± 5.577
Change from BL at Cycle 15 (n = 814)	0.78 ± 5.758
Change from BL at Cycle 18 (n = 732)	0.83 ± 5.797
Change from BL at Cycle 21 (n = 629)	0.89 ± 5.804
Change from BL at Cycle 24 (n = 583)	0.53 ± 5.903
Change from BL at Cycle 27 (n = 523)	0.71 ± 6.064
Change from BL at Cycle 30 (n = 524)	0.60 ± 5.961
Change from BL at Cycle 33 (n = 478)	0.67 ± 6.209
Change from BL at Cycle 36 (n = 436)	0.52 ± 5.687
Change from BL at Cycle 39 (n = 430)	0.26 ± 5.927
Change from BL at Cycle 42 (n = 393)	0.31 ± 6.038
Change from BL at Cycle 45 (n = 368)	0.34 ± 6.049
Change from BL at Cycle 48 (n = 344)	0.28 ± 6.227
Change from BL at Cycle 51 (n = 319)	0.23 ± 5.931
Change from BL at Cycle 54 (n = 289)	-0.06 ± 6.090
Change from BL at Cycle 57 (n = 294)	0.21 ± 5.925
Change from BL at Cycle 60 (n = 268)	0.01 ± 6.100
Change from BL at Cycle 63 (n = 275)	-0.06 ± 6.178
Change from BL at Cycle 66 (n = 247)	-0.07 ± 6.264
Change from BL at Cycle 69 (n = 243)	-0.47 ± 6.476
Change from BL at Cycle 72 (n = 224)	-0.50 ± 6.378
Change from BL at Cycle 75 (n = 217)	-0.40 ± 6.391
Change from BL at Cycle 78 (n = 211)	-0.18 ± 6.197
Change from BL at Cycle 81 (n = 197)	-0.29 ± 6.046
Change from BL at Cycle 84 (n = 186)	-0.48 ± 6.022
Change from BL at Cycle 87 (n = 180)	-0.08 ± 6.250
Change from BL at Cycle 90 (n = 152)	0.16 ± 6.587
Change from BL at Cycle 93 (n = 135)	0.58 ± 6.161
Change from BL at Cycle 96 (n = 111)	1.27 ± 6.663
Change from BL at Cycle 99 (n = 89)	0.46 ± 6.651
Change from BL at Cycle 102 (n = 73)	0.96 ± 6.327
Change from BL at Cycle 105 (n = 59)	1.14 ± 5.922
Change from BL at Cycle 108 (n = 46)	1.42 ± 6.902
Change from BL at Cycle 111 (n = 38)	0.32 ± 6.507
Change from BL at Cycle 114 (n = 20)	-0.25 ± 6.439
Change from BL at Cycle 117 (n = 12)	-0.58 ± 5.316
Change from BL at Cycle 120 (n = 4)	-2.00 ± 3.916
Change from BL at Cycle 123 (n = 2)	-5.00 ± 2.828
Change from BL at End of Treatment (n = 463)	-0.50 ± 6.132
Change from BL at Day 28 of Follow-Up (n = 586)	-0.70 ± 6.558

No statistical analyses for this end point

Secondary: Change from Baseline in FACT-B Questionnaire Breast Cancer Subscale Score Over the Course of the Study

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End point title

Change from Baseline in FACT-B Questionnaire Breast Cancer Subscale Score Over the Course of the Study

End point description

The FACT-B questionnaire (version 4) was administered only to female participants to assess quality of life in five subscales: physical, social, emotional, and functional well-being, and breast cancer. For the breast cancer subscale, participants were given a series of 10 statements and were asked to rate how true each statement was for them during the past 7 days on a 5-point scale ranging from 0 (not at all) to 4 (very much). The calculated FACT-B breast cancer subscale score, ranging from 0 to 40, was the sum of the scores for each statement only if at least 50% of items had been answered; the higher the score, the better the quality of life. Baseline was defined as the last non-missing measurement taken prior to first dose of study treatment (including unscheduled assessments). Post-baseline values were summarized for planned visits only.

End point type

Secondary

End point timeframe

End point values	Pertuzumab + Trastuzumab + Taxane
Number of subjects analysed	1429
Units: Score on a scale
arithmetic mean (standard deviation)
Baseline (BL): Absolute Value at Visit (n = 1326)	24.98 ± 6.296
Change from BL at Cycle 3 (n = 1181)	0.48 ± 5.101
Change from BL at Cycle 6 (n = 1117)	-0.11 ± 5.759
Change from BL at Cycle 9 (n = 1027)	0.52 ± 5.633
Change from BL at Cycle 12 (n = 910)	0.89 ± 5.770
Change from BL at Cycle 15 (n = 808)	1.16 ± 6.180
Change from BL at Cycle 18 (n = 729)	1.30 ± 6.043
Change from BL at Cycle 21 (n = 625)	1.30 ± 5.898
Change from BL at Cycle 24 (n = 580)	1.39 ± 6.231
Change from BL at Cycle 27 (n = 520)	1.17 ± 6.043
Change from BL at Cycle 30 (n = 521)	1.34 ± 5.968
Change from BL at Cycle 33 (n = 477)	1.34 ± 6.113
Change from BL at Cycle 36 (n = 435)	1.33 ± 6.030
Change from BL at Cycle 39 (n = 427)	1.12 ± 6.210
Change from BL at Cycle 42 (n = 393)	1.11 ± 6.499
Change from BL at Cycle 45 (n = 366)	1.13 ± 6.414
Change from BL at Cycle 48 (n = 343)	1.00 ± 6.679
Change from BL at Cycle 51 (n = 316)	0.99 ± 6.430
Change from BL at Cycle 54 (n = 291)	0.76 ± 6.555
Change from BL at Cycle 57 (n = 294)	0.70 ± 6.355
Change from BL at Cycle 60 (n = 267)	0.80 ± 6.586
Change from BL at Cycle 63 (n = 274)	1.32 ± 6.960
Change from BL at Cycle 66 (n = 246)	0.74 ± 6.822
Change from BL at Cycle 69 (n = 241)	0.54 ± 6.532
Change from BL at Cycle 72 (n = 223)	0.50 ± 7.142
Change from BL at Cycle 75 (n = 216)	0.85 ± 6.925
Change from BL at Cycle 78 (n = 210)	1.22 ± 6.899
Change from BL at Cycle 81 (n = 196)	0.27 ± 7.100
Change from BL at Cycle 84 (n = 184)	0.55 ± 6.690
Change from BL at Cycle 87 (n = 178)	1.17 ± 6.882
Change from BL at Cycle 90 (n = 150)	0.51 ± 7.313
Change from BL at Cycle 93 (n = 132)	0.30 ± 7.163
Change from BL at Cycle 96 (n = 110)	0.65 ± 6.240
Change from BL at Cycle 99 (n = 87)	1.19 ± 6.957
Change from BL at Cycle 102 (n = 72)	0.56 ± 6.189
Change from BL at Cycle 105 (n = 58)	0.68 ± 6.399
Change from BL at Cycle 108 (n = 45)	0.19 ± 6.982
Change from BL at Cycle 111 (n = 36)	0.01 ± 6.814
Change from BL at Cycle 114 (n = 19)	-1.67 ± 5.963
Change from BL at Cycle 117 (n = 11)	-1.56 ± 5.842
Change from BL at Cycle 120 (n = 4)	-2.17 ± 6.055
Change from BL at Cycle 123 (n = 2)	-7.94 ± 7.307
Change from BL at End of Treatment (n = 459)	0.88 ± 6.574
Change from BL at Day 28 of Follow-Up (n = 576)	0.66 ± 6.477

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Baseline until 28 days after last dose of study treatment. The median (full range) duration of exposure to any study treatment was 16.2 (0.0-86.4) months.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

Pertuzumab + Trastuzumab + Taxane

Reporting group description

Serious adverse events	Pertuzumab + Trastuzumab + Taxane
Total subjects affected by serious adverse events
subjects affected / exposed	535 / 1436 (37.26%)
number of deaths (all causes)	658
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
B-cell type acute leukemia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Breast neoplasm
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Bronchial carcinoma
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Cancer pain
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Endometrial cancer
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Gastrointestinal stromal tumour
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Lentigo maligna
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Lobular breast carcinoma in situ
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Lung neoplasm
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Metastatic squamous cell carcinoma
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Neuroendocrine tumour of the lung
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Papillary thyroid cancer
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Renal cancer
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Squamous cell carcinoma
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Thyroid cancer
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Tumour embolism
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Vascular disorders
Hypertensive crisis
subjects affected / exposed	4 / 1436 (0.28%)
occurrences causally related to treatment / all	0 / 4
deaths causally related to treatment / all	0 / 0
Deep vein thrombosis
subjects affected / exposed	3 / 1436 (0.21%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Haematoma
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Hypertension
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Hypotension
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	2 / 2
deaths causally related to treatment / all	0 / 0
Circulatory collapse
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Jugular vein thrombosis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Lymphoedema
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Subclavian vein thrombosis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Superior vena cava syndrome
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Thrombosis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Surgical and medical procedures
Internal fixation of fracture
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	1 / 2
deaths causally related to treatment / all	0 / 0
Abortion
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	18 / 1436 (1.25%)
occurrences causally related to treatment / all	7 / 21
deaths causally related to treatment / all	0 / 0
Asthenia
subjects affected / exposed	6 / 1436 (0.42%)
occurrences causally related to treatment / all	4 / 6
deaths causally related to treatment / all	0 / 0
General physical health deterioration
subjects affected / exposed	5 / 1436 (0.35%)
occurrences causally related to treatment / all	3 / 7
deaths causally related to treatment / all	0 / 0
Death
subjects affected / exposed	3 / 1436 (0.21%)
occurrences causally related to treatment / all	1 / 3
deaths causally related to treatment / all	1 / 3
Fatigue
subjects affected / exposed	3 / 1436 (0.21%)
occurrences causally related to treatment / all	1 / 3
deaths causally related to treatment / all	0 / 0
Chills
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Mucosal inflammation
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Catheter site inflammation
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Chest pain
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Device related thrombosis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Drug intolerance
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Inflammatory pain
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Influenza like illness
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Infusion site extravasation
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Malaise
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Nodule
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	20 / 1436 (1.39%)
occurrences causally related to treatment / all	4 / 20
deaths causally related to treatment / all	0 / 0
Hypersensitivity
subjects affected / exposed	5 / 1436 (0.35%)
occurrences causally related to treatment / all	1 / 5
deaths causally related to treatment / all	0 / 0
Reproductive system and breast disorders
Breast haematoma
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Ovarian cyst
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Uterine prolapse
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	16 / 1436 (1.11%)
occurrences causally related to treatment / all	1 / 16
deaths causally related to treatment / all	0 / 0
Pulmonary embolism
subjects affected / exposed	11 / 1436 (0.77%)
occurrences causally related to treatment / all	0 / 11
deaths causally related to treatment / all	0 / 0
Pleural effusion
subjects affected / exposed	6 / 1436 (0.42%)
occurrences causally related to treatment / all	0 / 8
deaths causally related to treatment / all	0 / 0
Lung disorder
subjects affected / exposed	3 / 1436 (0.21%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Pneumothorax
subjects affected / exposed	3 / 1436 (0.21%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Asthma
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	1 / 2
deaths causally related to treatment / all	0 / 0
Pneumonitis
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 1
Respiratory failure
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Aspiration
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Cough
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Pleuritic pain
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Pneumothorax spontaneous
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Psychiatric disorders
Agitation
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Depression
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Anxiety
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Anxiety disorder
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Confusional state
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Delirium
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Psychiatric decompensation
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Psychotic disorder
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Product issues
Device breakage
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Device loosening
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Investigations
Ejection fraction decreased
subjects affected / exposed	18 / 1436 (1.25%)
occurrences causally related to treatment / all	17 / 19
deaths causally related to treatment / all	0 / 0
Neutrophil count decreased
subjects affected / exposed	11 / 1436 (0.77%)
occurrences causally related to treatment / all	10 / 18
deaths causally related to treatment / all	0 / 0
White blood cell count decreased
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Blood creatinine increased
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Computerised tomogram abdomen abnormal
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Platelet count decreased
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Weight decreased
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	8 / 1436 (0.56%)
occurrences causally related to treatment / all	1 / 8
deaths causally related to treatment / all	0 / 0
Infusion related reaction
subjects affected / exposed	8 / 1436 (0.56%)
occurrences causally related to treatment / all	4 / 8
deaths causally related to treatment / all	0 / 0
Ankle fracture
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Femoral neck fracture
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Hip fracture
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Post procedural haemorrhage
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Rib fracture
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Carbon monoxide poisoning
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Chemical burns of eye
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Fall
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Foot fracture
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Fractured sacrum
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Humerus fracture
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Inflammation of wound
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Injury
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Limb injury
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Lower limb injury
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Multiple fractures
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Overdose
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Radiation injury
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Radius fracture
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Spinal fracture
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Toxicity to various agents
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Ulna fracture
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Upper limb fracture
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Wound
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Cardiac disorders
Cardiac failure
subjects affected / exposed	12 / 1436 (0.84%)
occurrences causally related to treatment / all	12 / 13
deaths causally related to treatment / all	1 / 1
Atrial fibrillation
subjects affected / exposed	8 / 1436 (0.56%)
occurrences causally related to treatment / all	4 / 10
deaths causally related to treatment / all	0 / 0
Atrial thrombosis
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Cardiac arrest
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 2
Cardiac failure congestive
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	1 / 2
deaths causally related to treatment / all	1 / 1
Left ventricular dysfunction
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	2 / 2
deaths causally related to treatment / all	0 / 0
Pericardial effusion
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Supraventricular tachycardia
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Acute coronary syndrome
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Cardiac failure chronic
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Cardiac tamponade
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Cardiovascular insufficiency
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Intracardiac mass
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Left ventricular failure
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Mitral valve disease
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Right ventricular failure
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	1 / 1
Sinus node dysfunction
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Tachycardia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Nervous system disorders
Ischaemic stroke
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 1
Seizure
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Aphasia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Ataxia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Cauda equina syndrome
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Cerebrovascular disorder
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Cognitive disorder
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Headache
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Hepatic encephalopathy
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	1 / 1
Hypoaesthesia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Intracranial pressure increased
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Neuropsychiatric lupus
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Presyncope
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Progressive supranuclear palsy
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Restless legs syndrome
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Spinal cord compression
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Transient global amnesia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Transverse sinus thrombosis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Tremor
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Trigeminal neuralgia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	71 / 1436 (4.94%)
occurrences causally related to treatment / all	21 / 75
deaths causally related to treatment / all	1 / 1
Neutropenia
subjects affected / exposed	47 / 1436 (3.27%)
occurrences causally related to treatment / all	5 / 56
deaths causally related to treatment / all	0 / 1
Anaemia
subjects affected / exposed	8 / 1436 (0.56%)
occurrences causally related to treatment / all	2 / 8
deaths causally related to treatment / all	0 / 0
Leukopenia
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	1 / 2
deaths causally related to treatment / all	0 / 0
Febrile bone marrow aplasia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Bone marrow failure
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Eye disorders
Cataract
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Glaucoma
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Retinal detachment
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	36 / 1436 (2.51%)
occurrences causally related to treatment / all	16 / 43
deaths causally related to treatment / all	0 / 0
Vomiting
subjects affected / exposed	7 / 1436 (0.49%)
occurrences causally related to treatment / all	2 / 8
deaths causally related to treatment / all	0 / 0
Colitis
subjects affected / exposed	4 / 1436 (0.28%)
occurrences causally related to treatment / all	3 / 4
deaths causally related to treatment / all	0 / 0
Abdominal pain
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Gastritis
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Pancreatitis
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 1
Rectal haemorrhage
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	1 / 2
deaths causally related to treatment / all	0 / 0
Anal fistula
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Crohn's disease
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Food poisoning
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Gastric ulcer perforation
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Haematemesis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Ileal stenosis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Large intestinal obstruction
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Large intestine polyp
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Oesophageal stenosis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Pancreatitis chronic
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Small intestinal obstruction
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Stomatitis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	4 / 1436 (0.28%)
occurrences causally related to treatment / all	0 / 4
deaths causally related to treatment / all	0 / 0
Cholecystitis acute
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Cholangitis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Cholangitis sclerosing
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Cholestasis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Hepatic failure
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	1 / 1
Hepatocellular injury
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Liver injury
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	1 / 2
deaths causally related to treatment / all	0 / 0
Pemphigus
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Rash
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Skin ulcer
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	7 / 1436 (0.49%)
occurrences causally related to treatment / all	3 / 8
deaths causally related to treatment / all	0 / 0
Renal failure
subjects affected / exposed	3 / 1436 (0.21%)
occurrences causally related to treatment / all	1 / 4
deaths causally related to treatment / all	0 / 0
Cystitis haemorrhagic
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Renal impairment
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	2 / 2
deaths causally related to treatment / all	0 / 0
Urinary tract obstruction
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Endocrine disorders
Hypogonadism
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Musculoskeletal and connective tissue disorders
Osteonecrosis of jaw
subjects affected / exposed	7 / 1436 (0.49%)
occurrences causally related to treatment / all	0 / 9
deaths causally related to treatment / all	0 / 0
Osteoarthritis
subjects affected / exposed	3 / 1436 (0.21%)
occurrences causally related to treatment / all	0 / 4
deaths causally related to treatment / all	0 / 0
Arthritis
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Bone pain
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Pain in extremity
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Spinal osteoarthritis
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Arthralgia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Back pain
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Fracture pain
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Myalgia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Neck pain
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Pathological fracture
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	26 / 1436 (1.81%)
occurrences causally related to treatment / all	4 / 30
deaths causally related to treatment / all	0 / 4
Cellulitis
subjects affected / exposed	15 / 1436 (1.04%)
occurrences causally related to treatment / all	4 / 19
deaths causally related to treatment / all	0 / 0
Urinary tract infection
subjects affected / exposed	15 / 1436 (1.04%)
occurrences causally related to treatment / all	3 / 15
deaths causally related to treatment / all	0 / 0
Neutropenic sepsis
subjects affected / exposed	10 / 1436 (0.70%)
occurrences causally related to treatment / all	1 / 10
deaths causally related to treatment / all	0 / 0
Sepsis
subjects affected / exposed	10 / 1436 (0.70%)
occurrences causally related to treatment / all	0 / 11
deaths causally related to treatment / all	0 / 3
Vascular device infection
subjects affected / exposed	9 / 1436 (0.63%)
occurrences causally related to treatment / all	0 / 9
deaths causally related to treatment / all	0 / 0
Device related infection
subjects affected / exposed	8 / 1436 (0.56%)
occurrences causally related to treatment / all	1 / 9
deaths causally related to treatment / all	0 / 0
Respiratory tract infection
subjects affected / exposed	7 / 1436 (0.49%)
occurrences causally related to treatment / all	1 / 7
deaths causally related to treatment / all	0 / 1
Erysipelas
subjects affected / exposed	6 / 1436 (0.42%)
occurrences causally related to treatment / all	3 / 8
deaths causally related to treatment / all	0 / 0
Upper respiratory tract infection
subjects affected / exposed	6 / 1436 (0.42%)
occurrences causally related to treatment / all	0 / 6
deaths causally related to treatment / all	0 / 0
Influenza
subjects affected / exposed	5 / 1436 (0.35%)
occurrences causally related to treatment / all	0 / 5
deaths causally related to treatment / all	0 / 0
Lower respiratory tract infection
subjects affected / exposed	5 / 1436 (0.35%)
occurrences causally related to treatment / all	1 / 5
deaths causally related to treatment / all	0 / 0
Gastroenteritis
subjects affected / exposed	4 / 1436 (0.28%)
occurrences causally related to treatment / all	0 / 4
deaths causally related to treatment / all	0 / 0
Arthritis bacterial
subjects affected / exposed	3 / 1436 (0.21%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Herpes zoster
subjects affected / exposed	3 / 1436 (0.21%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Pyelonephritis
subjects affected / exposed	3 / 1436 (0.21%)
occurrences causally related to treatment / all	0 / 4
deaths causally related to treatment / all	0 / 0
Viral infection
subjects affected / exposed	3 / 1436 (0.21%)
occurrences causally related to treatment / all	1 / 3
deaths causally related to treatment / all	0 / 0
Bacteraemia
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	1 / 2
deaths causally related to treatment / all	0 / 0
Diverticulitis
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	2 / 4
deaths causally related to treatment / all	0 / 0
Extradural abscess
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	1 / 2
deaths causally related to treatment / all	0 / 0
Gastroenteritis viral
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Infection
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Neutropenic infection
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	1 / 2
deaths causally related to treatment / all	0 / 0
Staphylococcal infection
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Wound infection
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Abscess limb
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Bacterial pyelonephritis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Biliary sepsis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Bronchitis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Catheter site infection
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Clostridial infection
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Clostridium colitis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Cystitis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Device related sepsis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Dysentery
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Enteritis infectious
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Enterocolitis bacterial
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Gangrene
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Gastrointestinal infection
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Hepatitis C
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Herpes zoster disseminated
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Large intestine infection
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Localised infection
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Lung abscess
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Meningitis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Nasopharyngitis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Necrotising fasciitis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Oesophageal candidiasis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	2 / 2
deaths causally related to treatment / all	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Paronychia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Peritonitis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Pharyngitis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Post procedural infection
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Pseudomonal sepsis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Pyomyositis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Salmonellosis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Septic shock
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 1
Sinusitis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Sinusitis fungal
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Soft tissue infection
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	2 / 2
deaths causally related to treatment / all	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Tooth infection
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Varicella
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	4 / 1436 (0.28%)
occurrences causally related to treatment / all	1 / 4
deaths causally related to treatment / all	0 / 0
Hyponatraemia
subjects affected / exposed	4 / 1436 (0.28%)
occurrences causally related to treatment / all	0 / 6
deaths causally related to treatment / all	0 / 0
Hypocalcaemia
subjects affected / exposed	3 / 1436 (0.21%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Hypophosphataemia
subjects affected / exposed	3 / 1436 (0.21%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Hypoglycaemia
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 1
Hypokalaemia
subjects affected / exposed	2 / 1436 (0.14%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Gout
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Hypoalbuminaemia
subjects affected / exposed	1 / 1436 (0.07%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Pertuzumab + Trastuzumab + Taxane
Total subjects affected by non serious adverse events
subjects affected / exposed	1394 / 1436 (97.08%)
Vascular disorders
Hypertension
subjects affected / exposed	152 / 1436 (10.58%)
occurrences all number	217
Hot flush
subjects affected / exposed	129 / 1436 (8.98%)
occurrences all number	165
Lymphoedema
subjects affected / exposed	98 / 1436 (6.82%)
occurrences all number	121
General disorders and administration site conditions
Fatigue
subjects affected / exposed	457 / 1436 (31.82%)
occurrences all number	829
Asthenia
subjects affected / exposed	426 / 1436 (29.67%)
occurrences all number	1123
Mucosal inflammation
subjects affected / exposed	287 / 1436 (19.99%)
occurrences all number	490
Pyrexia
subjects affected / exposed	258 / 1436 (17.97%)
occurrences all number	387
Oedema peripheral
subjects affected / exposed	257 / 1436 (17.90%)
occurrences all number	344
Influenza like illness
subjects affected / exposed	96 / 1436 (6.69%)
occurrences all number	136
Pain
subjects affected / exposed	81 / 1436 (5.64%)
occurrences all number	114
Chills
subjects affected / exposed	75 / 1436 (5.22%)
occurrences all number	84
Chest pain
subjects affected / exposed	74 / 1436 (5.15%)
occurrences all number	86
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	271 / 1436 (18.87%)
occurrences all number	410
Epistaxis
subjects affected / exposed	263 / 1436 (18.31%)
occurrences all number	360
Dyspnoea
subjects affected / exposed	195 / 1436 (13.58%)
occurrences all number	260
Oropharyngeal pain
subjects affected / exposed	124 / 1436 (8.64%)
occurrences all number	156
Rhinorrhoea
subjects affected / exposed	100 / 1436 (6.96%)
occurrences all number	135
Psychiatric disorders
Insomnia
subjects affected / exposed	157 / 1436 (10.93%)
occurrences all number	183
Depression
subjects affected / exposed	78 / 1436 (5.43%)
occurrences all number	94
Anxiety
subjects affected / exposed	75 / 1436 (5.22%)
occurrences all number	87
Investigations
Ejection fraction decreased
subjects affected / exposed	157 / 1436 (10.93%)
occurrences all number	215
Weight decreased
subjects affected / exposed	98 / 1436 (6.82%)
occurrences all number	115
Nervous system disorders
Headache
subjects affected / exposed	328 / 1436 (22.84%)
occurrences all number	542
Neuropathy peripheral
subjects affected / exposed	328 / 1436 (22.84%)
occurrences all number	537
Paraesthesia
subjects affected / exposed	221 / 1436 (15.39%)
occurrences all number	366
Dizziness
subjects affected / exposed	205 / 1436 (14.28%)
occurrences all number	271
Dysgeusia
subjects affected / exposed	141 / 1436 (9.82%)
occurrences all number	193
Peripheral sensory neuropathy
subjects affected / exposed	120 / 1436 (8.36%)
occurrences all number	158
Taste disorder
subjects affected / exposed	75 / 1436 (5.22%)
occurrences all number	92
Neurotoxicity
subjects affected / exposed	72 / 1436 (5.01%)
occurrences all number	118
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	312 / 1436 (21.73%)
occurrences all number	521
Neutropenia
subjects affected / exposed	222 / 1436 (15.46%)
occurrences all number	439
Leukopenia
subjects affected / exposed	84 / 1436 (5.85%)
occurrences all number	162
Eye disorders
Lacrimation increased
subjects affected / exposed	169 / 1436 (11.77%)
occurrences all number	220
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	974 / 1436 (67.83%)
occurrences all number	2753
Nausea
subjects affected / exposed	512 / 1436 (35.65%)
occurrences all number	918
Vomiting
subjects affected / exposed	340 / 1436 (23.68%)
occurrences all number	531
Constipation
subjects affected / exposed	235 / 1436 (16.36%)
occurrences all number	347
Stomatitis
subjects affected / exposed	210 / 1436 (14.62%)
occurrences all number	326
Abdominal pain
subjects affected / exposed	206 / 1436 (14.35%)
occurrences all number	314
Abdominal pain upper
subjects affected / exposed	149 / 1436 (10.38%)
occurrences all number	187
Dyspepsia
subjects affected / exposed	141 / 1436 (9.82%)
occurrences all number	170
Haemorrhoids
subjects affected / exposed	79 / 1436 (5.50%)
occurrences all number	92
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	693 / 1436 (48.26%)
occurrences all number	813
Rash
subjects affected / exposed	365 / 1436 (25.42%)
occurrences all number	596
Pruritus
subjects affected / exposed	292 / 1436 (20.33%)
occurrences all number	466
Dry skin
subjects affected / exposed	167 / 1436 (11.63%)
occurrences all number	208
Nail disorder
subjects affected / exposed	163 / 1436 (11.35%)
occurrences all number	197
Erythema
subjects affected / exposed	137 / 1436 (9.54%)
occurrences all number	183
Onycholysis
subjects affected / exposed	118 / 1436 (8.22%)
occurrences all number	179
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	75 / 1436 (5.22%)
occurrences all number	94
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	328 / 1436 (22.84%)
occurrences all number	550
Myalgia
subjects affected / exposed	284 / 1436 (19.78%)
occurrences all number	476
Back pain
subjects affected / exposed	220 / 1436 (15.32%)
occurrences all number	289
Muscle spasms
subjects affected / exposed	196 / 1436 (13.65%)
occurrences all number	292
Pain in extremity
subjects affected / exposed	195 / 1436 (13.58%)
occurrences all number	248
Bone pain
subjects affected / exposed	135 / 1436 (9.40%)
occurrences all number	185
Musculoskeletal pain
subjects affected / exposed	128 / 1436 (8.91%)
occurrences all number	157
Infections and infestations
Nasopharyngitis
subjects affected / exposed	183 / 1436 (12.74%)
occurrences all number	309
Urinary tract infection
subjects affected / exposed	180 / 1436 (12.53%)
occurrences all number	294
Upper respiratory tract infection
subjects affected / exposed	164 / 1436 (11.42%)
occurrences all number	269
Influenza
subjects affected / exposed	110 / 1436 (7.66%)
occurrences all number	155
Conjunctivitis
subjects affected / exposed	99 / 1436 (6.89%)
occurrences all number	125
Rhinitis
subjects affected / exposed	93 / 1436 (6.48%)
occurrences all number	117
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	274 / 1436 (19.08%)
occurrences all number	447
Hypokalaemia
subjects affected / exposed	76 / 1436 (5.29%)
occurrences all number	122

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

02 Jan 2012

Version 2. Key changes included the following: • Change of inclusion criteria to allow inclusion of patients with a baseline LVEF of at least 50%. • Exclusion of patients with alkaline phosphatase levels > 2.5 × the ULN (> 5 × ULN in patients with liver metastases, or >10 × ULN in patients with bone metastases). • Update of background and rationale to include efficacy and safety data from CLEOPATRA. • Change the definition of time to response from the time from the date of randomization to the date of first CR or PR to the time from date of enrolment to date of first CR or PR. • Update of criteria for elevated liver function tests. • Update of safety analyses to include all enrolled patients.

30 Aug 2012

Version 3. Key changes included the following: • Redefinition of the end of study to 45 months after the last patient has been enrolled into the study or all patients in the study have withdrawn consent, or died, or if the study is prematurely terminated by the Sponsor, whichever occurs first. • Inclusion of patients who, prior to study entry had received up to two lines of hormonal therapies for metastatic or locally recurrent disease, one of which may have been in combination with everolimus. • Inclusion of patients with central nervous system (CNS) metastases if they were stable in the 3 months prior to screening after receiving local therapy but without anti-HER2 therapy. • Reduction of the time from major surgery to randomization from 28 days to 14 days based on recommendation from the Steering Committee for the PERTAIN study. • Reduction in the time from receipt of intravenous (IV) antibiotics prior to randomization from 14 days to 7 days based on recommendation from the PERTAIN Steering Committee. • Increase of the flexibility in the timing and order of administration of study medications. • Increase of the number of interim analyses from 3 to 5 planned analyses. • Update of the study rationale to include the latest CLEOPATRA study OS results. • Extension of the interval duration for the scheduling of tumor assessments after 36 months. • Increase of the defined timeline for scheduling of tumor assessments (excluding electrocardiogram [ECG]) to within 7 days of the scheduled visit. • Removal of the requirement for HER2 status to be measured within 28 days of enrolment if a previous result is available. • Update of the timeframe for reporting of SAEs. • Update of the Schedule of Assessments (SoA) to increase the number of days within which visits could occur before/after scheduled treatment day from ±3 to ±7 days.

09 May 2014

Version 4. Key changes included the following: • Updated guidance on the recommended pregnancy follow-up for trastuzumab and pregnancy testing technique. • Update of the study background to include CLEOPATRA OS results and US approval for neoadjuvant treatment. • Addition of an annual review of safety data by the iDMC following completion of enrollment. • Change in timing of follow-up visits to approximately every 3 months. • Inclusion of analysis of adverse event of special interest (AESI) and description of baseline covariates to be explored for ORR assessment. • Update to permit radiotherapy of brain metastases.

20 Nov 2015

Version 5. Key changes included the following: • Extension of the follow-up period of the study from 45 months to at least 60 months after the last patient had been enrolled into the study or all patients in the study had withdrawn consent, or died, whichever occurred first. • Update of the definition for abnormal liver function test (alanine aminotransferase [ALT] and aspartate aminotransferase [AST] elevations) SAEs.

21 Nov 2018

Version 6. Key changes included the following: • Reduction in the frequency of imaging procedures for response assessments in long-term responders from every six cycles (approximately 4.5 months) in patients who remained progression free after 36 months to at least every 12 cycles following discussions at the iDMC meeting on 28 June 2018. • Reduction in the frequency of iDMC meetings from annually to approximately once per year. • Update of the policy on post-trial access to pertuzumab.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Multicenter, Open-Label, Single-Arm Study of Pertuzumab in Combination with Trastuzumab and a Taxane in First Line Treatment of Patients with HER2-Positive Advanced (Metastatic or Locally Recurrent) Breast Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overview of the Number of Participants with at Least One Treatment-Emergent Adverse Event, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE v4.0)

Primary: Overview of the Number of Participants with at Least One Treatment-Emergent Adverse Event, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE v4.0)

Primary: Number of Participants Who Died Over the Course of the Study by Reported Cause of Death (Adverse Events Leading to Death by System Organ Class and Preferred Term)

Primary: Number of Participants Who Died Over the Course of the Study by Reported Cause of Death (Adverse Events Leading to Death by System Organ Class and Preferred Term)

Primary: Number of Participants Who Died Within 6 Months of Starting Study Treatment by Reported Cause of Death (Adverse Events Leading to Death by System Organ Class and Preferred Term)

Primary: Number of Participants Who Died Within 6 Months of Starting Study Treatment by Reported Cause of Death (Adverse Events Leading to Death by System Organ Class and Preferred Term)

Primary: Number of Participants with Grade ≥3 Treatment-Emergent Adverse Events, Occurring in ≥1% of Participants by System Organ Class and Preferred Term

Primary: Number of Participants with Grade ≥3 Treatment-Emergent Adverse Events, Occurring in ≥1% of Participants by System Organ Class and Preferred Term

Primary: Number of Participants with Treatment-Emergent Adverse Events of Any Grade That Were Related to Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥10% of Participants by System Organ Class

Primary: Number of Participants with Treatment-Emergent Adverse Events of Any Grade That Were Related to Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥10% of Participants by System Organ Class

Primary: Number of Participants with Grade ≥3 Treatment-Emergent Adverse Events That Were Related to Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥0.5% of Participants by Preferred Term

Primary: Number of Participants with Grade ≥3 Treatment-Emergent Adverse Events That Were Related to Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥0.5% of Participants by Preferred Term

Primary: Number of Participants with Treatment-Emergent Adverse Events Leading to Discontinuation of Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥0.2% of Participants by Preferred Term

Primary: Number of Participants with Treatment-Emergent Adverse Events Leading to Discontinuation of Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥0.2% of Participants by Preferred Term

Primary: Number of Participants with Treatment-Emergent Adverse Events Leading to Dose Interruption of Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥0.5% of Participants by Preferred Term

Primary: Number of Participants with Treatment-Emergent Adverse Events Leading to Dose Interruption of Study Treatment (Pertuzumab, Trastuzumab, or Taxane), Occurring in ≥0.5% of Participants by Preferred Term

Primary: Number of Participants with Treatment-Emergent Adverse Events to Monitor of Any Grade, Occurring in ≥5% of Participants by Category

Primary: Number of Participants with Treatment-Emergent Adverse Events to Monitor of Any Grade, Occurring in ≥5% of Participants by Category

Primary: Number of Participants with Grade ≥3 Treatment-Emergent Adverse Events to Monitor, Occurring in ≥0.5% of Participants by Category and Preferred Term

Primary: Number of Participants with Grade ≥3 Treatment-Emergent Adverse Events to Monitor, Occurring in ≥0.5% of Participants by Category and Preferred Term

Primary: Number of Participants with Treatment-Emergent Adverse Events of Special Interest by Category and Preferred Term

Primary: Number of Participants with Treatment-Emergent Adverse Events of Special Interest by Category and Preferred Term

Primary: Subgroup Analysis by Region of Enrollment: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

Primary: Subgroup Analysis by Region of Enrollment: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

Primary: Subgroup Analysis by Age (≤65 vs. >65 Years): Overview of Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), TEAEs Leading to Death, Grade ≥3 TEAEs, Any-Grade and Grade ≥3 TEAEs Related to Pertuzumab, and TEAEs to Monitor

Primary: Subgroup Analysis by Age (≤65 vs. >65 Years): Overview of Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), TEAEs Leading to Death, Grade ≥3 TEAEs, Any-Grade and Grade ≥3 TEAEs Related to Pertuzumab, and TEAEs to Monitor

Primary: Subgroup Analysis by Taxane Chemotherapy: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), TEAEs Leading to Death, Grade ≥3 TEAEs, Any-Grade and Grade ≥3 TEAEs Related to Pertuzumab, and TEAEs to Monitor

Primary: Subgroup Analysis by Taxane Chemotherapy: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), TEAEs Leading to Death, Grade ≥3 TEAEs, Any-Grade and Grade ≥3 TEAEs Related to Pertuzumab, and TEAEs to Monitor

Primary: Subgroup Analysis by ECOG Performance Status at Baseline: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

Primary: Subgroup Analysis by ECOG Performance Status at Baseline: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

Primary: Subgroup Analysis by Visceral Disease at Baseline: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

Primary: Subgroup Analysis by Visceral Disease at Baseline: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

Primary: Subgroup Analysis by Prior (Neo)Adjuvant Chemotherapy: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

Primary: Subgroup Analysis by Prior (Neo)Adjuvant Chemotherapy: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

Primary: Subgroup Analysis by Hormone Receptor Status at Baseline: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

Primary: Subgroup Analysis by Hormone Receptor Status at Baseline: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

Primary: Subgroup Analysis by Previous Trastuzumab Therapy: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

Primary: Subgroup Analysis by Previous Trastuzumab Therapy: Overview of the Percentage of Participants with Serious Treatment-Emergent Adverse Events (TEAEs), Grade ≥3 TEAEs, and Grade ≥3 TEAEs Related to Pertuzumab

Primary: Number of Participants with a Congestive Heart Failure Event

Primary: Number of Participants with a Congestive Heart Failure Event

Primary: Time to Onset of the First Episode of Congestive Heart Failure

Primary: Time to Onset of the First Episode of Congestive Heart Failure

Primary: Change from Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study

Primary: Change from Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study

Primary: Number of Participants by Change from Baseline in Left Ventricular Ejection Fraction (LVEF) Categories Over the Course of the Study

Primary: Number of Participants by Change from Baseline in Left Ventricular Ejection Fraction (LVEF) Categories Over the Course of the Study

Primary: Number of Participants with Laboratory Abnormalities in Hematology and Coagulation Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to NCI-CTC v4.0

Primary: Number of Participants with Laboratory Abnormalities in Hematology and Coagulation Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to NCI-CTC v4.0

Primary: Number of Participants with Laboratory Abnormalities in Hematology and Coagulation Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to Normal Range Criteria

Primary: Number of Participants with Laboratory Abnormalities in Hematology and Coagulation Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to Normal Range Criteria

Primary: Number of Participants with Laboratory Abnormalities in Biochemistry Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to NCI-CTC v4.0

Primary: Number of Participants with Laboratory Abnormalities in Biochemistry Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to NCI-CTC v4.0

Primary: Number of Participants with Laboratory Abnormalities in Biochemistry Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to Normal Range Criteria

Primary: Number of Participants with Laboratory Abnormalities in Biochemistry Parameters: Shift From Baseline to the Worst Post-Baseline Grade According to Normal Range Criteria

Secondary: Progression-Free Survival, as Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)

Secondary: Progression-Free Survival, as Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)

Secondary: Subgroup Analysis by Region of Enrollment: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Secondary: Subgroup Analysis by Region of Enrollment: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Secondary: Subgroup Analysis by Age (≤65 vs. >65 Years): Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Secondary: Subgroup Analysis by Age (≤65 vs. >65 Years): Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Secondary: Subgroup Analysis by ECOG Performance Status at Baseline: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Secondary: Subgroup Analysis by ECOG Performance Status at Baseline: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Secondary: Subgroup Analysis by Taxane Chemotherapy: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Secondary: Subgroup Analysis by Taxane Chemotherapy: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Secondary: Subgroup Analysis by Visceral Disease at Baseline: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Secondary: Subgroup Analysis by Visceral Disease at Baseline: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Secondary: Subgroup Analysis by Prior (Neo)Adjuvant Chemotherapy: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Secondary: Subgroup Analysis by Prior (Neo)Adjuvant Chemotherapy: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Secondary: Subgroup Analysis by Hormone Receptor Status at Baseline: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Secondary: Subgroup Analysis by Hormone Receptor Status at Baseline: Progression-Free Survival, as Assessed by the Investigator Using RECIST v1.1

Clinical Trial Results:
A Multicenter, Open-Label, Single-Arm Study of Pertuzumab in Combination with Trastuzumab and a Taxane in First Line Treatment of Patients with HER2-Positive Advanced (Metastatic or Locally Recurrent) Breast Cancer