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Clinical Trial Results:
A randomised, multicenter, multinational Phase II study on trastuzumab plus docetaxel versus trastuzumab plus docetaxel plus pertuzumab versus trastuzumab plus pertuzumab in patients with locally advanced, inflammatory or early stage HER2 positive breast cancer

Summary
EudraCT number	2007-001105-13
Trial protocol	ES AT IT PL GB SE
Global end of trial date	22 Sep 2014

Results information
Results version number	v1
This version publication date	19 Mar 2016
First version publication date	19 Mar 2016
Other versions	v2

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

WO20697

ISRCTN number

US NCT number

NCT00545688

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse124, Basel, Switzerland, CH-4070

Public contact

F.Hoffmann-LaRocheAG, Roche Trial Information Hotline, +41 616878333, global.trial_information@roche.com

Scientific contact

F.Hoffmann-LaRocheAG, Roche Trial Information Hotline, +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 Oct 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

22 Sep 2014

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective was to make a preliminary assessment of the efficacy of neoadjuvant treatment with trastuzumab plus docetaxel (T+D), as compared to trastuzumab, pertuzumab plus docetaxel (Ptz+T+D), or to pertuzumab plus trastuzumab (Ptz+T), and to compare pertuzumab plus docetaxel (Ptz+D) with trastuzumab, pertuzumab plus docetaxel (Ptz+T+D), in participants with T2-4d human epidermal growth factor receptor 2 (HER2) -positive breast cancer.

Protection of trial subjects

This study was conducted in full conformance with the principles of the ‘Declaration of Helsinki’ (and its subsequent amendments) or with the local laws and regulations of the country in which the research was conducted; whichever provided greater protection to the individual. In countries in which good clinical practice (GCP) guidelines exist, sponsor and the investigators strictly adhered to the stated provisions in these guidelines.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Dec 2007

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 54

Country: Number of subjects enrolled

Spain: 48

Country: Number of subjects enrolled

Sweden: 12

Country: Number of subjects enrolled

United Kingdom: 2

Country: Number of subjects enrolled

Austria: 3

Country: Number of subjects enrolled

Italy: 58

Country: Number of subjects enrolled

Australia: 1

Country: Number of subjects enrolled

Brazil: 39

Country: Number of subjects enrolled

Canada: 27

Country: Number of subjects enrolled

Switzerland: 7

Country: Number of subjects enrolled

Mexico: 1

Country: Number of subjects enrolled

Peru: 9

Country: Number of subjects enrolled

China: 39

Country: Number of subjects enrolled

Korea, Republic of: 37

Country: Number of subjects enrolled

Russian Federation: 61

Country: Number of subjects enrolled

Thailand: 19

Worldwide total number of subjects

417

EEA total number of subjects

177

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)

385

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

A total of 107, 107, 107, and 96 participants (total 417) were randomized to Arms Trastuzumab plus (+) Docetaxel (T+ D), Trastuzumab+Pertuzumab+Docetaxel (T+Ptz+D), Trastuzumab+Pertuzumab (T+Ptz), and Pertuzumab+Docetaxel (Ptz+D), respectively and were included in intent-to-treat population (as randomized).

Screening details

3 participants did not receive correct treatment, as randomized, and 1 (in Arm T + D) did not receive any treatment. Safety population (as treated) included 107, 107, 108, and 94 participants in Arms 'T+D', 'T+Ptz+D', 'T+Ptz', and 'Ptz+D', respectively. Participant flow was available for "As Treated" participants.

Period 1 title

Baseline Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Trastuzumab + Docetaxel

Arm description

Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab intravenous (IV) infusion at a loading dose of 8 milligrams per kilogram (mg/kg) on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 milligrams per square meter (mg/m^2) on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by 5-fluorouracil 600 mg/m^2 IV, epirubicin 90 mg/m^2 IV, and cyclophosphamide 600 mg/m^2 IV (FEC) on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5−7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.

Arm type

Experimental

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 8 mg/kg IV infusion on Day 1 of Cycle 1and maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 during pre-operative period and 6 mg/kg IV on Day 1 of Cycles 5-18 in the T + D and T + Ptz + D arms. In the Ptz + D arm, 6 mg/kg IV on Day 1 of adjuvant period and every 3 weeks thereafter for Cycles 5-21.

Trastuzumab+Pertuzumab+Docetaxel

Arm description

Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5−7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.

Arm type

Experimental

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

RO4368451

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 840 mg on Day 1 of Cycle 1 and 420 mg on Day 1 of Cycles 2-4.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 8 mg/kg IV infusion on Day 1 of Cycle 1 and maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 during pre-operative period and 6 mg/kg IV on Day 1 of Cycles 5-18 in the T + D and T + Ptz + D arms. In the Ptz + D arm, 6 mg/kg IV on Day 1 of adjuvant period and every 3 weeks thereafter for Cycles 5-21.

Trastuzumab+Pertuzumab

Arm description

Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6−8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.

Arm type

Active comparator

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

RO4368451

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 840 mg on Day 1 of Cycle 1 and 420 mg on Day 1 of Cycles 2-4.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 8 mg/kg IV infusion on Day 1 of Cycle 1 and maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 during pre-operative period and 6 mg/kg IV on Day 1 of Cycles 5-18 in the T + D and T + Ptz + D arms. In the Ptz + D arm, 6 mg/kg IV on Day 1 of adjuvant period and every 3 weeks thereafter for Cycles 5-21.

Pertuzumab+Docetaxel

Arm description

Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5−7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.

Arm type

Active comparator

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

RO4368451

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 840 mg on Day 1 of Cycle 1 and 420 mg on Day 1 of Cycles 2-4.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 8 mg/kg IV infusion on Day 1 of Cycle 1 and maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 during pre-operative period and 6 mg/kg IV on Day 1 of Cycles 5-18 in the T + D and T + Ptz + D arms. In the Ptz + D arm, 6 mg/kg IV on Day 1 of adjuvant period and every 3 weeks thereafter for Cycles 5-21.

Number of subjects in period 1	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Started	107	107	107	96
Completed	107	107	108	94
Not completed	1	0	0	2
Received wrong dosage	-	-	-	2
Unknown reason	1	-	-	-
Joined	1	0	1	0
Received wrong dosage	1	-	1	-

Period 2 title

Neo-Adjuvant Treatment Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Trastuzumab + Docetaxel

Arm description

Arm type

Experimental

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab+Pertuzumab+Docetaxel

Arm description

Arm type

Experimental

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

RO4368451

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 840 mg on Day 1 of Cycle 1 and 420 mg on Day 1 of Cycles 2-4.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab+Pertuzumab

Arm description

Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6−8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.

Arm type

Active comparator

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

RO4368451

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 840 mg on Day 1 of Cycle 1 and 420 mg on Day 1 of Cycles 2-4.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 8 mg/kg IV infusion on Day 1 of Cycle 1 and maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 during pre-operative period and 6 mg/kg IV on Day 1 of Cycles 5-18 in the T + D and T + Ptz + D arms. In the Ptz + D arm, 6 mg/kg IV on Day 1 of adjuvant period and every 3 weeks thereafter for Cycles 5-21.

Pertuzumab+Docetaxel

Arm description

Arm type

Active comparator

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

RO4368451

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 840 mg on Day 1 of Cycle 1 and 420 mg on Day 1 of Cycles 2-4.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 8 mg/kg IV infusion on Day 1 of Cycle 1 and maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 during pre-operative period and 6 mg/kg IV on Day 1 of Cycles 5-18 in the T + D and T + Ptz + D arms. In the Ptz + D arm, 6 mg/kg IV on Day 1 of adjuvant period and every 3 weeks thereafter for Cycles 5-21.

Number of subjects in period 2	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Started	107	107	108	94
Completed	103	102	94	88
Not completed	4	5	14	6
Disease progression	-	1	7	2
Death	-	1	-	-
Refused treatment	1	1	4	1
Adverse event	-	-	2	2
Unknown reason	1	-	-	-
Lost to follow-up	1	-	-	-
Protocol deviation	1	2	1	1

Period 3 title

Adjuvant Treatment Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Trastuzumab + Docetaxel

Arm description

Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by 5-fluorouracil 600 mg/m^2 IV, epirubicin 90 mg/m^2 IV, and cyclophosphamide 600 mg/m^2 IV (FEC) on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5−7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.

Arm type

Experimental

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 8 mg/kg IV infusion on Day 1 of Cycle 1 and maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 during pre-operative period and 6 mg/kg IV on Day 1 of Cycles 5-18 in the T + D and T + Ptz + D arms. In the Ptz + D arm, 6 mg/kg IV on Day 1 of adjuvant period and every 3 weeks thereafter for Cycles 5-21.

Trastuzumab+Pertuzumab+Docetaxel

Arm description

Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5−7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.

Arm type

Experimental

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

RO4368451

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 840 mg on Day 1 of Cycle 1 and 420 mg on Day 1 of Cycles 2-4.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 8 mg/kg IV infusion on Day 1 of Cycle 1 and maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 during pre-operative period and 6 mg/kg IV on Day 1 of Cycles 5-18 in the T + D and T + Ptz + D arms. In the Ptz + D arm, 6 mg/kg IV on Day 1 of adjuvant period and every 3 weeks thereafter for Cycles 5-21.

Trastuzumab+Pertuzumab

Arm description

Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6−8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.

Arm type

Active comparator

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

RO4368451

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 840 mg on Day 1 of Cycle 1 and 420 mg on Day 1 of Cycles 2-4.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 8 mg/kg IV infusion on Day 1 of Cycle 1 and maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 during pre-operative period and 6 mg/kg IV on Day 1 of Cycles 5-18 in the T + D and T + Ptz + D arms. In the Ptz + D arm, 6 mg/kg IV on Day 1 of adjuvant period and every 3 weeks thereafter for Cycles 5-21.

Pertuzumab+Docetaxel

Arm description

Arm type

Active comparator

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

RO4368451

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 840 mg on Day 1 of Cycle 1 and 420 mg on Day 1 of Cycles 2-4.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Loading dose of 8 mg/kg IV infusion on Day 1 of Cycle 1 and maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 during pre-operative period and 6 mg/kg IV on Day 1 of Cycles 5-18 in the T + D and T + Ptz + D arms. In the Ptz + D arm, 6 mg/kg IV on Day 1 of adjuvant period and every 3 weeks thereafter for Cycles 5-21.

Number of subjects in period 3	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Started	103	102	94	88
Completed	98	94	90	74
Not completed	5	8	4	14
Disease progression	3	3	-	7
Refused treatment	1	1	1	5
Adverse event	-	3	2	2
Unknown reason	-	1	-	-
Lost to follow-up	1	-	1	-

Period 4 title

Follow-Up Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Trastuzumab + Docetaxel

Arm description

During the post-treatment follow-up period no trial drug was administered.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Trastuzumab+Pertuzumab+Docetaxe

Arm description

During the post-treatment follow-up period no trial drug was administered.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Trastuzumab+Pertuzumab

Arm description

During the post-treatment follow-up period no trial drug was administered.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Pertuzumab+Docetaxel

Arm description

During the post-treatment follow-up period no trial drug was administered.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 4	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxe	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Started	98	102	98	87
Completed	77	83	78	60
Not completed	21	19	20	27
Disease progression	6	5	9	9
Death	4	2	2	6
Refused treatment	6	2	-	2
Violation of selection criteria	-	2	-	1
Unspecified reason	2	5	6	8
Lost to follow-up	3	3	3	1

Baseline characteristics

Top of page

Reporting group title

Baseline Period

Reporting group description

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
Justification: Subjects included in the Baseline period were the Safety Analysis Population.

Reporting group values	Baseline Period	Total
Number of subjects	417	417
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	49.8 ± 10.4	-
Gender categorical
Units: Subjects
Female	417	417
Male	0	0

End points

Top of page

Reporting group title

Trastuzumab + Docetaxel

Reporting group description

Reporting group title

Trastuzumab+Pertuzumab+Docetaxel

Reporting group description

Reporting group title

Trastuzumab+Pertuzumab

Reporting group description

Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6−8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.

Reporting group title

Pertuzumab+Docetaxel

Reporting group description

Reporting group title

Trastuzumab + Docetaxel

Reporting group description

Reporting group title

Trastuzumab+Pertuzumab+Docetaxel

Reporting group description

Reporting group title

Trastuzumab+Pertuzumab

Reporting group description

Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6−8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.

Reporting group title

Pertuzumab+Docetaxel

Reporting group description

Reporting group title

Trastuzumab + Docetaxel

Reporting group description

Reporting group title

Trastuzumab+Pertuzumab+Docetaxel

Reporting group description

Reporting group title

Trastuzumab+Pertuzumab

Reporting group description

Reporting group title

Pertuzumab+Docetaxel

Reporting group description

Reporting group title

Trastuzumab + Docetaxel

Reporting group description

During the post-treatment follow-up period no trial drug was administered.

Reporting group title

Trastuzumab+Pertuzumab+Docetaxe

Reporting group description

During the post-treatment follow-up period no trial drug was administered.

Reporting group title

Trastuzumab+Pertuzumab

Reporting group description

During the post-treatment follow-up period no trial drug was administered.

Reporting group title

Pertuzumab+Docetaxel

Reporting group description

During the post-treatment follow-up period no trial drug was administered.

Primary: Percentage of Participants Achieving Pathological Complete Response (pCR)

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End point title

Percentage of Participants Achieving Pathological Complete Response (pCR)

End point description

pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants with invalid/missing pCR assessments were defined as non-responders. Intent-To-Treat (ITT) Population included all randomized participants who received any amount of study medication. Analysis was performed according to initial randomization.

End point type

Primary

End point timeframe

Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	107	107	107	96
Units: percentage of participants
number (confidence interval 95%)	29 (20.6 to 38.5)	45.8 (36.1 to 55.7)	16.8 (10.3 to 25.3)	24 (15.8 to 33.7)

Statistical Analysis 1

Comparison groups

Trastuzumab + Docetaxel v Trastuzumab+Pertuzumab+Docetaxel

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0094 ^[1]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response rates

Point estimate

16.82

Confidence interval

level

95%

sides

2-sided

lower limit

3.5

upper limit

30.1

Notes
[1] - Cochran-Mantel-Haenszel test stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen and or progesterone positivity (either positive versus both negative).

Statistical Analysis 2

Comparison groups

Trastuzumab + Docetaxel v Trastuzumab+Pertuzumab+Docetaxel

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0141 ^[2]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[2] - Cochran-Mantel-Haenszel test (with Simes multiplicity adjustment) stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen and or progesterone positivity (either positive versus both negative).

Statistical Analysis 3

Comparison groups

Trastuzumab + Docetaxel v Trastuzumab+Pertuzumab

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0198 ^[3]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response rate

Point estimate

-12.15

Confidence interval

level

95%

sides

2-sided

lower limit

-23.8

upper limit

-0.5

Notes
[3] - Cochran-Mantel-Haenszel test stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen and or progesterone positivity (either positive versus both negative).

Statistical Analysis 4

Comparison groups

Trastuzumab + Docetaxel v Trastuzumab+Pertuzumab

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0198 ^[4]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[4] - Cochran-Mantel-Haenszel test with Simes multiplicity adjustment was used.

Statistical Analysis 5

Comparison groups

Trastuzumab+Pertuzumab+Docetaxel v Pertuzumab+Docetaxel

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.001 ^[5]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response rates

Point estimate

-21.84

Confidence interval

level

95%

sides

2-sided

lower limit

-35.1

upper limit

-8.5

Notes
[5] - Cochran-Mantel-Haenszel test stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen and or progesterone positivity (either positive versus both negative).

Statistical Analysis 6

Comparison groups

Trastuzumab+Pertuzumab+Docetaxel v Pertuzumab+Docetaxel

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.003 ^[6]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[6] - Cochran-Mantel-Haenszel test with Simes multiplicity adjustment.

Primary: Percentage of Participants Achieving pCR by Breast Cancer Type

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End point title

Percentage of Participants Achieving pCR by Breast Cancer Type ^[7]

End point description

pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Based on the type of breast cancer participants were categorized as those with 1. Operable breast cancer, 2. Inflammatory breast cancer and 3. Locally advanced breast cancer. Participants with invalid/missing pCR assessments were defined as non-responders.Analysis was performed on ITT population according to initial randomization. Number (n) equal (=) number of participants included in the specified type of breast cancer.

End point type

Primary

End point timeframe

Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

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: No statistical analysis was performed per protocol since this endpoint was sub-group analysis.

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	107	107	107	96
Units: percentage of participants
number (confidence interval 95%)
Operable Breast Cancer (n=64,65,65,60)	23.4 (13.8 to 35.7)	47.7 (35.1 to 60.5)	16.9 (8.8 to 28.3)	26.7 (16.1 to 39.7)
Inflammatory Breast Cancer (n=7,10,7,5)	14.3 (0.4 to 57.9)	40 (12.2 to 73.8)	28.6 (3.7 to 71)	40 (5.3 to 85.3)
Locally Advance Breast Cancer (n=36,32,35,31)	41.7 (25.5 to 59.2)	43.8 (26.4 to 62.3)	14.3 (4.8 to 30.3)	16.1 (5.5 to 33.7)

No statistical analyses for this end point

Primary: Percentage of Participants Achieving pCR by Hormone Receptor Status

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End point title

Percentage of Participants Achieving pCR by Hormone Receptor Status ^[8]

End point description

pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants were classified as Estrogen and/or Progesterone positive (+ve), Estrogen and/or Progesterone negative (-ve) or receptor status unknown. Participants with invalid/missing pCR assessments were defined as non-responders. 99999 to 99999= There were no participants in this category.Analysis was performed on ITT population according to initial randomization. n = number of participants included in the specified hormone receptor status.

End point type

Primary

End point timeframe

Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

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: No statistical analysis was performed per protocol since this endpoint was sub-group analysis.

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	107	107	107	96
Units: percentage of participants
number (confidence interval 95%)
Estrogen and/or Progesterone +ve (n=50,50,51,46)	20 (10 to 33.7)	26 (14.6 to 40.3)	5.9 (1.2 to 16.2)	17.4 (7.8 to 31.4)
Estrogen and/or Progesterone -ve (n=57,57,55,50)	36.8 (24.4 to 50.7)	63.2 (49.3 to 75.6)	27.3 (16.1 to 41)	30 (17.9 to 44.6)
Receptor Status Unknown (0,0,1,0)	99999 (99999 to 99999)	99999 (99999 to 99999)	0 (0 to 97.5)	99999 (99999 to 99999)

No statistical analyses for this end point

Primary: Percentage of Participants Achieving pCR by Lymph Node Status

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End point title

Percentage of Participants Achieving pCR by Lymph Node Status ^[9]

End point description

pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Lymph node status was defined as either negative lymph node at surgery or positive lymph node at surgery. Participants with invalid/missing pCR assessments were defined as non-responders.Analysis was performed on ITT population according to initial randomization.

End point type

Primary

End point timeframe

Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

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: No statistical analysis was performed per protocol since this endpoint was sub-group analysis.

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	107	107	107	96
Units: percentage of participants
number (not applicable)
pCR achieved and Negative Lymph Nodes at Surgery	21.5	39.3	11.2	17.7
pCR achieved and Positive Lymph Nodes at Surgery	7.5	6.5	5.6	6.3

No statistical analyses for this end point

Primary: Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS)

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End point title

Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS) ^[10]

End point description

pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants with invalid/missing pCR assessments were defined as non-responders.Analysis was performed on ITT population according to initial randomization.

End point type

Primary

End point timeframe

Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

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: No statistical analysis was performed per protocol since this endpoint was sub-group analysis.

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	107	107	107	96
Units: percentage of participants
number (not applicable)
pCR Achieved and No residual DCIS/LCIS at Surgery	16.8	36.4	9.3	17.7
pCR Achieved and Residual DCIS/LCIS at Surgery	12.1	9.3	7.5	6.3

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography

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End point title

Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography

End point description

Tumor assessments were made based upon the Response Evaluation Criteria in Solid Tumors (RECIST) criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for primary breast tumor using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is greater than (>)0 at screening or cycle 1 Day 1; PR: if measurement is at least a 30 percent (%) decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline.Analysis was performed on ITT population according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.

End point type

Secondary

End point timeframe

Baseline up to Cycle 4 (assessed at baseline, Day 1 of Cycles 1-4 Pre-Surgery)

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	71	58	61	47
Units: percentage of participants
number (not applicable)
CR	18.3	19	13.1	19.1
PR	49.3	46.6	36.1	46.8
SD	31	32.8	44.3	34
PD	1.4	1.7	6.6	0

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography

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End point title

Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography

End point description

Tumor assessments were made based on the RECIST criteria - version 1.0 The overall response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined. Ana

End point type

Secondary

End point timeframe

Baseline up to Cycle 4 (assessed at baseline, Day 1 of Cycles 1-4 Pre-Surgery)

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	71	53	55	43
Units: percentage of participants
number (not applicable)
CR	18.3	18.9	12.7	18.6
PR	49.3	49.1	34.5	46.5
SD	31	30.2	45.5	34.9
PD	1.4	1.9	7.3	0

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination

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End point title

Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination

End point description

Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for primary breast tumor using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels. (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined.Analysis was performed on ITT population according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.

End point type

Secondary

End point timeframe

Baseline up to Cycle 4 (assessed at baseline, Day 1 of Cycles 1-4 Pre-Surgery)

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	99	101	102	91
Units: percentage of participants
number (not applicable)
CR	23.2	30.7	16.7	20.9
PR	56.6	57.4	51	50.5
SD	20.2	11.9	30.4	28.6
PD	0	0	2	0

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination

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End point title

Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination

End point description

Clinical response was determined based on tumor measurements by sponsor in combination with tumor response assessment by investigator. Tumor assessments were made based on the RECIST criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels. Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment. Overall response is derived based on the sum total of breast tumors and all nodes examined. Analysis was performed on ITT population according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.

End point type

Secondary

End point timeframe

Baseline up to Cycle 4 (assessed at baseline, Day 1 of Cycles 1-4 Pre-Surgery)

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	97	100	98	88
Units: percentage of participants
number (not applicable)
CR	21.6	25	11.2	15.9
PR	59.8	63	55.1	58
SD	17.5	12	31.6	26.1
PD	1	0	2	0

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography

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End point title

Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography

End point description

End point type

Secondary

End point timeframe

Baseline up to Cycle 4 (assessed at baseline, Day 1 of Cycles 1-4 Pre-Surgery)

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	71	58	61	47
Units: percentage of participants
number (confidence interval 95%)
Primary Breast Tumor (n=71,58,61,47)	67.6 (55.5 to 78.2)	65.5 (51.9 to 77.5)	49.2 (36.1 to 62.3)	66 (50.7 to 79.1)
Overall Response (n=71,53,55,43)	67.6 (55.5 to 78.2)	67.9 (53.7 to 80.1)	47.3 (33.7 to 61.2)	65.1 (49.1 to 79)

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination

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End point title

Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination

End point description

Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment. Primary breast tumor clinical response is based on primary breast tumor assessment. Overall response is derived based on the sum total of breast tumors and all nodes examined.Analysis was performed on ITT population according to initial randomization. Number of participants analyzed = participants evaluable for this outcome and n = number participants analyzed in the specified category.

End point type

Secondary

End point timeframe

Baseline up to Cycle 4 (assessed at baseline, Day 1 of Cycles 1-4 Pre-Surgery)

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	99	101	102	91
Units: percentage of participants
number (confidence interval 95%)
Primary Breast Tumor (n=99,101,102,91)	79.8 (70.5 to 87.2)	88.1 (80.2 to 93.7)	67.6 (57.7 to 76.6)	71.4 (61 to 80.4)
Overall Response (n=97,100,98,88)	81.4 (72.3 to 88.6)	88 (80 to 93.6)	66.3 (56.1 to 75.6)	73.9 (63.4 to 82.7)

No statistical analyses for this end point

Secondary: Time to Clinical Response During Neo-Adjuvant Treatment Period

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End point title

Time to Clinical Response During Neo-Adjuvant Treatment Period

End point description

Time to clinical response was defined as the time from the date of first dose received to the date of assessment of clinical response. Time to Clinical response was determined by Kaplan-Meier estimates. Tumor assessments were made based on the RECIST criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment.Analysis was performed on ITT population according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.

End point type

Secondary

End point timeframe

Baseline up to Cycle 4 (assessed at baseline, Day 1 of Cycles 1-4 Pre-Surgery)

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	99	101	102	91
Units: months
median (confidence interval 80%)	6.3 (6 to 7)	6.3 (4 to 7)	6.9 (6 to 9)	7.3 (6 to 9)

No statistical analyses for this end point

Secondary: Percentage of Participants With Progressive Disease During Neo-Adjuvant Treatment Period

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End point title

Percentage of Participants With Progressive Disease During Neo-Adjuvant Treatment Period

End point description

Tumor assessments were made based upon the Response Evaluation Criteria in Solid Tumors (RECIST) criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: PD: if lesion is at least a 20 % increased from measurements at baseline. Percentage of participants along with 95% Confidence Interval (CI) for one sample binomial using Pearson-Clopper method were reported. Missing investigator assessments were considered as no progressive disease. Analysis was performed on ITT population according to initial randomization.

End point type

Secondary

End point timeframe

Baseline up to Cycle 4 (assessed at baseline, Day 1 of Cycles 1-4 Pre-Surgery)

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	107	107	107	96
Units: percentage of participants
number (confidence interval 80%)	0 (0 to 3.4)	0.9 (0 to 5.1)	7.5 (3.3 to 14.2)	2.1 (0.3 to 7.3)

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Breast Conserving Surgery For Whom Mastectomy Was Planned

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End point title

Percentage of Participants Achieving Breast Conserving Surgery For Whom Mastectomy Was Planned

End point description

Breast Conserving Surgery (BCS) was defined as quadrantectomy, lumpectomy, no surgery, sentinel node biopsy, axillary surgical resection or other method of avoiding mastectomy. Analysis was performed on ITT population according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.

End point type

Secondary

End point timeframe

Surgery (Within 2 weeks after Cycle 4)

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	62	56	61	60
Units: percentage of participants
number (confidence interval 95%)	22.6 (12.9 to 35)	23.2 (13 to 36.4)	18 (9.4 to 30)	31.7 (20.3 to 45)

No statistical analyses for this end point

Secondary: Percentage of Participants Who Were Progression Free and Disease Free

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End point title

Percentage of Participants Who Were Progression Free and Disease Free

End point description

Disease-free survival (DFS) was defined as time from first date of no disease to first documentation of PD or death. Participants without progression after surgery were considered Disease Free. Progression-free survival (PFS) was defined as time from date of randomization to first documentation of PD or death. Any evidence of contralateral disease in-situ was not considered as PD. Participants who were withdrawn from study without documented progression and for whom evaluations were made, were censored at date of last assessment when the participant was known to be free from progressive disease or were disease free. Participants without post baseline assessments but known to be alive were censored at the time of randomization. Analysis was performed on ITT population according to initial randomization. Analysis was performed on ITT population according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.

End point type

Secondary

End point timeframe

Randomization up to a maximum of 329 weeks

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	107	107	107	96
Units: percentage of participants
number (not applicable)
Progression Free	82.2	84.1	74.8	75
Disease Free	82.5	85.1	80.2	76.1

No statistical analyses for this end point

Secondary: Progression Free and Disease Free Survival

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End point title

Progression Free and Disease Free Survival

End point description

DFS was defined as the time from the first date of no disease (date of surgery) to the first documentation of PD or death. Participants without progression after surgery were considered Disease Free. Any evidence of contralateral disease in-situ was not considered as PD. PFS was defined as the time from the date of randomization to the first documentation of PD or death. Any evidence of contralateral disease in-situ was not considered as PD. DFS and PFS were determined using Kaplan-Meier estimates. 99999 (99999-99999) = Data not available. Median and corresponding 80% confidence interval were not achieved due to the low number of events in this patient population, as expected. Analysis was performed on ITT population according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.

End point type

Secondary

End point timeframe

Randomization up to a maximum of 329 weeks

End point values	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Number of subjects analysed	107	107	107	96
Units: months
median (confidence interval 95%)
Progression Free	99999 (99999 to 99999)	71 (71 to 76)	99999 (99999 to 99999)	99999 (99999 to 99999)
Disease Free	99999 (99999 to 99999)	67.2 (67 to 72)	99999 (99999 to 99999)	99999 (99999 to 99999)

Statistical Analysis 7

Statistical analysis description

HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity. Comparison is for PFS.

Comparison groups

Trastuzumab + Docetaxel v Trastuzumab+Pertuzumab+Docetaxel

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2983

Method

Cox proportional Hazards

Parameter type

Hazard ratio (HR)

Point estimate

0.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.34

upper limit

1.4

Statistical Analysis 8

Statistical analysis description

HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity. Comparison is for PFS.

Comparison groups

Trastuzumab + Docetaxel v Trastuzumab+Pertuzumab

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.4722

Method

Cochran-Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

1.25

Confidence interval

level

95%

sides

2-sided

lower limit

0.68

upper limit

2.3

Statistical Analysis 9

Statistical analysis description

HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity. Comparison is for PFS.

Comparison groups

Trastuzumab+Pertuzumab+Docetaxel v Pertuzumab+Docetaxel

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0268

Method

Cochran-Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

2.05

Confidence interval

level

95%

sides

2-sided

lower limit

1.07

upper limit

3.93

Statistical Analysis 10

Statistical analysis description

HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity. Comparison is for DFS.

Comparison groups

Trastuzumab + Docetaxel v Pertuzumab+Docetaxel

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1805

Method

Cochran-Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

1.27

Statistical Analysis 11

Statistical analysis description

HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity. Comparison is for DFS.

Comparison groups

Trastuzumab + Docetaxel v Trastuzumab+Pertuzumab+Docetaxel

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5901

Method

Cochran-Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.42

upper limit

1.64

Statistical Analysis 12

Statistical analysis description

HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity. Comparison is for DFS.

Comparison groups

Trastuzumab+Pertuzumab+Docetaxel v Pertuzumab+Docetaxel

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.025

Method

Cochran-Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

2.16

Confidence interval

level

95%

sides

2-sided

lower limit

1.08

upper limit

4.32

Adverse events

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Timeframe for reporting adverse events

Adverse events were recorded from the date of Screening until the clinical cutoff date 20th October 2014 up to 7 years.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Trastuzumab+Docetaxel

Reporting group description

Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5−7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.

Reporting group title

Trastuzumab+Pertuzumab+Docetaxel

Reporting group description

Reporting group title

Trastuzumab+Pertuzumab

Reporting group description

Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6−8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.

Reporting group title

Pertuzumab+Docetaxel

Reporting group description

Serious adverse events	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Total subjects affected by serious adverse events
subjects affected / exposed	21 / 107 (19.63%)	22 / 107 (20.56%)	19 / 108 (17.59%)	21 / 94 (22.34%)
number of deaths (all causes)	6	8	9	8
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage
subjects affected / exposed	1 / 107 (0.93%)	0 / 107 (0.00%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Venous insufficiency
subjects affected / exposed	0 / 107 (0.00%)	1 / 107 (0.93%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 107 (0.93%)	1 / 107 (0.93%)	2 / 108 (1.85%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	1 / 1	1 / 1	3 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 107 (0.00%)	1 / 107 (0.93%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Metrorrhagia
subjects affected / exposed	1 / 107 (0.93%)	0 / 107 (0.00%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst ruptured
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	0 / 108 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian disorder
subjects affected / exposed	1 / 107 (0.93%)	0 / 107 (0.00%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine haemorrhage
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	0 / 108 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	1 / 107 (0.93%)	0 / 107 (0.00%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 107 (0.00%)	1 / 107 (0.93%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Left ventricular dysfunction
subjects affected / exposed	0 / 107 (0.00%)	3 / 107 (2.80%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 107 (0.00%)	1 / 107 (0.93%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Dural arteriovenous fistula
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	0 / 108 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	10 / 107 (9.35%)	8 / 107 (7.48%)	4 / 108 (3.70%)	12 / 94 (12.77%)
occurrences causally related to treatment / all	10 / 10	8 / 8	4 / 4	16 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 107 (0.93%)	6 / 107 (5.61%)	3 / 108 (2.78%)	6 / 94 (6.38%)
occurrences causally related to treatment / all	2 / 2	6 / 6	4 / 4	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	2 / 107 (1.87%)	0 / 107 (0.00%)	0 / 108 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal strangulated hernia
subjects affected / exposed	0 / 107 (0.00%)	1 / 107 (0.93%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 107 (0.00%)	1 / 107 (0.93%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis fulminant
subjects affected / exposed	0 / 107 (0.00%)	1 / 107 (0.93%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash papular
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin mass
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	0 / 107 (0.00%)	1 / 107 (0.93%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Neutropenic infection
subjects affected / exposed	1 / 107 (0.93%)	1 / 107 (0.93%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 107 (0.93%)	0 / 107 (0.00%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 107 (0.00%)	2 / 107 (1.87%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 107 (0.93%)	0 / 107 (0.00%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	2 / 107 (1.87%)	0 / 107 (0.00%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast abscess
subjects affected / exposed	1 / 107 (0.93%)	0 / 107 (0.00%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	0 / 108 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 107 (0.00%)	1 / 107 (0.93%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
H1N1 influenza
subjects affected / exposed	0 / 107 (0.00%)	1 / 107 (0.93%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	1 / 107 (0.93%)	0 / 107 (0.00%)	0 / 108 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	0 / 108 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	1 / 108 (0.93%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 107 (0.00%)	0 / 107 (0.00%)	0 / 108 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Total subjects affected by non serious adverse events
subjects affected / exposed	107 / 107 (100.00%)	105 / 107 (98.13%)	101 / 108 (93.52%)	94 / 94 (100.00%)
Vascular disorders
Hot flush
subjects affected / exposed	11 / 107 (10.28%)	12 / 107 (11.21%)	8 / 108 (7.41%)	7 / 94 (7.45%)
occurrences all number	13	12	8	7
Lymphoedema
subjects affected / exposed	4 / 107 (3.74%)	6 / 107 (5.61%)	12 / 108 (11.11%)	5 / 94 (5.32%)
occurrences all number	4	6	13	6
Flushing
subjects affected / exposed	6 / 107 (5.61%)	5 / 107 (4.67%)	5 / 108 (4.63%)	5 / 94 (5.32%)
occurrences all number	8	14	10	5
Hypertension
subjects affected / exposed	5 / 107 (4.67%)	6 / 107 (5.61%)	4 / 108 (3.70%)	3 / 94 (3.19%)
occurrences all number	6	6	4	7
General disorders and administration site conditions
Fatigue
subjects affected / exposed	35 / 107 (32.71%)	35 / 107 (32.71%)	34 / 108 (31.48%)	37 / 94 (39.36%)
occurrences all number	93	68	66	70
Mucosal inflammation
subjects affected / exposed	28 / 107 (26.17%)	33 / 107 (30.84%)	18 / 108 (16.67%)	28 / 94 (29.79%)
occurrences all number	45	60	28	43
Asthenia
subjects affected / exposed	22 / 107 (20.56%)	29 / 107 (27.10%)	19 / 108 (17.59%)	23 / 94 (24.47%)
occurrences all number	62	66	52	54
Pyrexia
subjects affected / exposed	16 / 107 (14.95%)	25 / 107 (23.36%)	21 / 108 (19.44%)	14 / 94 (14.89%)
occurrences all number	17	32	26	19
Oedema peripheral
subjects affected / exposed	12 / 107 (11.21%)	7 / 107 (6.54%)	18 / 108 (16.67%)	9 / 94 (9.57%)
occurrences all number	18	7	19	10
Chills
subjects affected / exposed	8 / 107 (7.48%)	4 / 107 (3.74%)	10 / 108 (9.26%)	2 / 94 (2.13%)
occurrences all number	9	5	12	2
Chest pain
subjects affected / exposed	4 / 107 (3.74%)	2 / 107 (1.87%)	4 / 108 (3.70%)	6 / 94 (6.38%)
occurrences all number	5	2	4	7
Pain
subjects affected / exposed	2 / 107 (1.87%)	3 / 107 (2.80%)	3 / 108 (2.78%)	7 / 94 (7.45%)
occurrences all number	3	3	3	7
Oedema
subjects affected / exposed	1 / 107 (0.93%)	0 / 107 (0.00%)	6 / 108 (5.56%)	4 / 94 (4.26%)
occurrences all number	1	0	7	4
General disorders
subjects affected / exposed	17 / 107 (15.89%)	16 / 107 (14.95%)	15 / 108 (13.89%)	26 / 94 (27.66%)
occurrences all number	43	29	39	47
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	2 / 107 (1.87%)	6 / 107 (5.61%)	12 / 108 (11.11%)	6 / 94 (6.38%)
occurrences all number	3	7	21	7
Reproductive system and breast disorders
Menstruation irregular
subjects affected / exposed	7 / 107 (6.54%)	4 / 107 (3.74%)	10 / 108 (9.26%)	9 / 94 (9.57%)
occurrences all number	7	4	10	9
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	11 / 107 (10.28%)	9 / 107 (8.41%)	19 / 108 (17.59%)	12 / 94 (12.77%)
occurrences all number	16	11	24	14
Epistaxis
subjects affected / exposed	6 / 107 (5.61%)	11 / 107 (10.28%)	6 / 108 (5.56%)	6 / 94 (6.38%)
occurrences all number	9	19	9	9
Oropharyngeal pain
subjects affected / exposed	7 / 107 (6.54%)	9 / 107 (8.41%)	2 / 108 (1.85%)	10 / 94 (10.64%)
occurrences all number	11	10	3	12
Dyspnoea
subjects affected / exposed	5 / 107 (4.67%)	7 / 107 (6.54%)	7 / 108 (6.48%)	4 / 94 (4.26%)
occurrences all number	6	9	8	4
Psychiatric disorders
Insomnia
subjects affected / exposed	14 / 107 (13.08%)	13 / 107 (12.15%)	8 / 108 (7.41%)	14 / 94 (14.89%)
occurrences all number	18	17	13	23
Anxiety
subjects affected / exposed	2 / 107 (1.87%)	3 / 107 (2.80%)	6 / 108 (5.56%)	0 / 94 (0.00%)
occurrences all number	2	3	9	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	9 / 107 (8.41%)	2 / 107 (1.87%)	2 / 108 (1.85%)	5 / 94 (5.32%)
occurrences all number	10	2	2	5
Weight increased
subjects affected / exposed	4 / 107 (3.74%)	2 / 107 (1.87%)	9 / 108 (8.33%)	1 / 94 (1.06%)
occurrences all number	4	2	9	1
Aspartate aminotransferase increased
subjects affected / exposed	9 / 107 (8.41%)	0 / 107 (0.00%)	2 / 108 (1.85%)	2 / 94 (2.13%)
occurrences all number	10	0	2	2
Injury, poisoning and procedural complications
Radiation skin injury
subjects affected / exposed	21 / 107 (19.63%)	19 / 107 (17.76%)	22 / 108 (20.37%)	24 / 94 (25.53%)
occurrences all number	22	22	24	25
Infusion related reaction
subjects affected / exposed	6 / 107 (5.61%)	7 / 107 (6.54%)	8 / 108 (7.41%)	8 / 94 (8.51%)
occurrences all number	7	8	18	13
Seroma
subjects affected / exposed	6 / 107 (5.61%)	7 / 107 (6.54%)	4 / 108 (3.70%)	5 / 94 (5.32%)
occurrences all number	7	7	5	5
Procedural pain
subjects affected / exposed	2 / 107 (1.87%)	3 / 107 (2.80%)	6 / 108 (5.56%)	2 / 94 (2.13%)
occurrences all number	2	4	7	2
Incision site pain
subjects affected / exposed	1 / 107 (0.93%)	2 / 107 (1.87%)	3 / 108 (2.78%)	5 / 94 (5.32%)
occurrences all number	1	2	5	5
Cardiac disorders
Palpitations
subjects affected / exposed	2 / 107 (1.87%)	5 / 107 (4.67%)	7 / 108 (6.48%)	5 / 94 (5.32%)
occurrences all number	2	8	9	5
Left ventricular dysfunction
subjects affected / exposed	2 / 107 (1.87%)	6 / 107 (5.61%)	2 / 108 (1.85%)	5 / 94 (5.32%)
occurrences all number	2	6	2	6
Nervous system disorders
Headache
subjects affected / exposed	17 / 107 (15.89%)	14 / 107 (13.08%)	25 / 108 (23.15%)	22 / 94 (23.40%)
occurrences all number	25	22	41	34
Dysgeusia
subjects affected / exposed	16 / 107 (14.95%)	16 / 107 (14.95%)	14 / 108 (12.96%)	10 / 94 (10.64%)
occurrences all number	21	24	20	12
Peripheral sensory neuropathy
subjects affected / exposed	14 / 107 (13.08%)	10 / 107 (9.35%)	15 / 108 (13.89%)	14 / 94 (14.89%)
occurrences all number	17	11	18	14
Dizziness
subjects affected / exposed	8 / 107 (7.48%)	6 / 107 (5.61%)	14 / 108 (12.96%)	8 / 94 (8.51%)
occurrences all number	9	6	25	10
Neuropathy peripheral
subjects affected / exposed	10 / 107 (9.35%)	6 / 107 (5.61%)	4 / 108 (3.70%)	5 / 94 (5.32%)
occurrences all number	15	6	5	6
Paraesthesia
subjects affected / exposed	7 / 107 (6.54%)	2 / 107 (1.87%)	3 / 108 (2.78%)	5 / 94 (5.32%)
occurrences all number	8	2	3	10
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	80 / 107 (74.77%)	64 / 107 (59.81%)	46 / 108 (42.59%)	67 / 94 (71.28%)
occurrences all number	236	168	134	192
Leukopenia
subjects affected / exposed	24 / 107 (22.43%)	13 / 107 (12.15%)	13 / 108 (12.04%)	15 / 94 (15.96%)
occurrences all number	63	32	34	32
Anaemia
subjects affected / exposed	9 / 107 (8.41%)	6 / 107 (5.61%)	11 / 108 (10.19%)	12 / 94 (12.77%)
occurrences all number	14	7	14	14
Eye disorders
Lacrimation increased
subjects affected / exposed	3 / 107 (2.80%)	8 / 107 (7.48%)	6 / 108 (5.56%)	6 / 94 (6.38%)
occurrences all number	3	8	6	6
Gastrointestinal disorders
Nausea
subjects affected / exposed	70 / 107 (65.42%)	71 / 107 (66.36%)	52 / 108 (48.15%)	61 / 94 (64.89%)
occurrences all number	145	178	123	139
Diarrhoea
subjects affected / exposed	40 / 107 (37.38%)	55 / 107 (51.40%)	46 / 108 (42.59%)	52 / 94 (55.32%)
occurrences all number	72	107	96	96
Vomiting
subjects affected / exposed	31 / 107 (28.97%)	39 / 107 (36.45%)	31 / 108 (28.70%)	37 / 94 (39.36%)
occurrences all number	46	53	56	60
Stomatitis
subjects affected / exposed	12 / 107 (11.21%)	22 / 107 (20.56%)	21 / 108 (19.44%)	11 / 94 (11.70%)
occurrences all number	16	38	34	17
Abdominal pain upper
subjects affected / exposed	8 / 107 (7.48%)	9 / 107 (8.41%)	12 / 108 (11.11%)	12 / 94 (12.77%)
occurrences all number	10	9	13	14
Constipation
subjects affected / exposed	12 / 107 (11.21%)	14 / 107 (13.08%)	9 / 108 (8.33%)	6 / 94 (6.38%)
occurrences all number	26	20	12	7
Abdominal pain
subjects affected / exposed	9 / 107 (8.41%)	11 / 107 (10.28%)	8 / 108 (7.41%)	10 / 94 (10.64%)
occurrences all number	11	13	8	10
Haemorrhoids
subjects affected / exposed	5 / 107 (4.67%)	8 / 107 (7.48%)	8 / 108 (7.41%)	4 / 94 (4.26%)
occurrences all number	5	8	8	4
Dyspepsia
subjects affected / exposed	6 / 107 (5.61%)	6 / 107 (5.61%)	6 / 108 (5.56%)	5 / 94 (5.32%)
occurrences all number	12	11	13	6
Abdominal distension
subjects affected / exposed	1 / 107 (0.93%)	1 / 107 (0.93%)	2 / 108 (1.85%)	5 / 94 (5.32%)
occurrences all number	1	1	3	6
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	75 / 107 (70.09%)	73 / 107 (68.22%)	59 / 108 (54.63%)	65 / 94 (69.15%)
occurrences all number	79	79	59	66
Rash
subjects affected / exposed	26 / 107 (24.30%)	30 / 107 (28.04%)	22 / 108 (20.37%)	30 / 94 (31.91%)
occurrences all number	43	57	26	43
Nail disorder
subjects affected / exposed	17 / 107 (15.89%)	13 / 107 (12.15%)	16 / 108 (14.81%)	13 / 94 (13.83%)
occurrences all number	17	14	18	14
Pruritus
subjects affected / exposed	8 / 107 (7.48%)	5 / 107 (4.67%)	10 / 108 (9.26%)	8 / 94 (8.51%)
occurrences all number	9	7	10	9
Erythema
subjects affected / exposed	5 / 107 (4.67%)	6 / 107 (5.61%)	7 / 108 (6.48%)	11 / 94 (11.70%)
occurrences all number	7	7	15	13
Skin hyperpigmentation
subjects affected / exposed	5 / 107 (4.67%)	7 / 107 (6.54%)	2 / 108 (1.85%)	6 / 94 (6.38%)
occurrences all number	5	7	2	6
Urticaria
subjects affected / exposed	1 / 107 (0.93%)	6 / 107 (5.61%)	4 / 108 (3.70%)	7 / 94 (7.45%)
occurrences all number	1	9	5	7
Acne
subjects affected / exposed	3 / 107 (2.80%)	7 / 107 (6.54%)	2 / 108 (1.85%)	4 / 94 (4.26%)
occurrences all number	3	10	3	4
Dry skin
subjects affected / exposed	7 / 107 (6.54%)	2 / 107 (1.87%)	3 / 108 (2.78%)	2 / 94 (2.13%)
occurrences all number	9	2	4	2
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	24 / 107 (22.43%)	25 / 107 (23.36%)	29 / 108 (26.85%)	22 / 94 (23.40%)
occurrences all number	43	43	61	37
Arthralgia
subjects affected / exposed	16 / 107 (14.95%)	18 / 107 (16.82%)	13 / 108 (12.04%)	19 / 94 (20.21%)
occurrences all number	27	21	19	27
Musculoskeletal pain
subjects affected / exposed	13 / 107 (12.15%)	13 / 107 (12.15%)	5 / 108 (4.63%)	11 / 94 (11.70%)
occurrences all number	21	19	6	13
Bone pain
subjects affected / exposed	13 / 107 (12.15%)	11 / 107 (10.28%)	7 / 108 (6.48%)	8 / 94 (8.51%)
occurrences all number	20	21	11	10
Back pain
subjects affected / exposed	7 / 107 (6.54%)	7 / 107 (6.54%)	8 / 108 (7.41%)	11 / 94 (11.70%)
occurrences all number	8	7	12	12
Pain in extremity
subjects affected / exposed	9 / 107 (8.41%)	7 / 107 (6.54%)	7 / 108 (6.48%)	6 / 94 (6.38%)
occurrences all number	11	9	10	6
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	12 / 107 (11.21%)	9 / 107 (8.41%)	11 / 108 (10.19%)	13 / 94 (13.83%)
occurrences all number	14	12	15	19
Nasopharyngitis
subjects affected / exposed	12 / 107 (11.21%)	8 / 107 (7.48%)	7 / 108 (6.48%)	5 / 94 (5.32%)
occurrences all number	13	13	8	6
Pharyngitis
subjects affected / exposed	8 / 107 (7.48%)	4 / 107 (3.74%)	4 / 108 (3.70%)	5 / 94 (5.32%)
occurrences all number	8	5	4	6
Urinary tract infection
subjects affected / exposed	7 / 107 (6.54%)	4 / 107 (3.74%)	3 / 108 (2.78%)	6 / 94 (6.38%)
occurrences all number	10	4	4	6
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	19 / 107 (17.76%)	18 / 107 (16.82%)	15 / 108 (13.89%)	23 / 94 (24.47%)
occurrences all number	32	39	22	29

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Were there any global substantial amendments to the protocol? Yes

04 Dec 2007

1. Addition of a fourth treatment arm (Arm D), in order to evaluate the efficacy of pertuzumab, in the absence of trastuzumab. 2. Increase in the number of subjects participating in the study from 180 to 400, and corresponding increase in the number of centers, from 45-55 to 100. 3. Amendment of efficacy endpoints, hypothesis testing and analyses to reflect addition of Arm D and increased participant numbers. Addition of an exclusion criterion.

11 Dec 2008

Correction of the tumor-node-metastasis (TNM) classes used to classify participants’ disease for the stratification groups operable, locally advanced, or inflammatory cancer for this study.

27 Jun 2009

1. Updates to: the definition of post-menopausal women, the contraceptive requirements for women of child bearing potential as recommended by The Medicines and Healthcare Products Regulatory Agency (MHRA) in accordance with the ICH M3 guideline, and the pregnancy testing scheduling. 2. Clarification of clinical response definition.

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 randomised, multicenter, multinational Phase II study on trastuzumab plus docetaxel versus trastuzumab plus docetaxel plus pertuzumab versus trastuzumab plus pertuzumab in patients with locally advanced, inflammatory or early stage HER2 positive breast cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants Achieving Pathological Complete Response (pCR)

Primary: Percentage of Participants Achieving Pathological Complete Response (pCR)

Primary: Percentage of Participants Achieving pCR by Breast Cancer Type

Primary: Percentage of Participants Achieving pCR by Breast Cancer Type

Primary: Percentage of Participants Achieving pCR by Hormone Receptor Status

Primary: Percentage of Participants Achieving pCR by Hormone Receptor Status

Primary: Percentage of Participants Achieving pCR by Lymph Node Status

Primary: Percentage of Participants Achieving pCR by Lymph Node Status

Primary: Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS)

Primary: Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS)

Secondary: Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography

Secondary: Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography

Secondary: Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography

Secondary: Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography

Secondary: Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination

Secondary: Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination

Secondary: Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination

Secondary: Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination

Secondary: Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography

Secondary: Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography

Secondary: Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination

Secondary: Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination

Secondary: Time to Clinical Response During Neo-Adjuvant Treatment Period

Secondary: Time to Clinical Response During Neo-Adjuvant Treatment Period

Secondary: Percentage of Participants With Progressive Disease During Neo-Adjuvant Treatment Period

Secondary: Percentage of Participants With Progressive Disease During Neo-Adjuvant Treatment Period

Secondary: Percentage of Participants Achieving Breast Conserving Surgery For Whom Mastectomy Was Planned

Secondary: Percentage of Participants Achieving Breast Conserving Surgery For Whom Mastectomy Was Planned

Secondary: Percentage of Participants Who Were Progression Free and Disease Free

Secondary: Percentage of Participants Who Were Progression Free and Disease Free

Secondary: Progression Free and Disease Free Survival

Secondary: Progression Free and Disease Free Survival

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A randomised, multicenter, multinational Phase II study on trastuzumab plus docetaxel versus trastuzumab plus docetaxel plus pertuzumab versus trastuzumab plus pertuzumab in patients with locally advanced, inflammatory or early stage HER2 positive breast cancer