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Clinical Trial Results:
A phase III, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of atezolizumab or placebo in combination with neoadjuvant doxorubicin + cyclophosphamide followed by paclitaxel + trastuzumab + pertuzumab in early HER2-positive breast cancer.

Summary
EudraCT number	2018-001881-40
Trial protocol	DE CZ ES PL IT
Global end of trial date

Results information
Results version number	v2(current)
This version publication date	13 Mar 2022
First version publication date	06 Feb 2022
Other versions	v1
Version creation reason

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

BO40747

ISRCTN number

US NCT number

NCT03726879

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

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

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 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

Interim

Date of interim/final analysis

05 Feb 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

05 Feb 2021

Global end of trial reached?

Main objective of the trial

This study (also known as IMpassion050) is evaluating the efficacy and safety of atezolizumab compared with placebo when given in combination with neoadjuvant dose-dense anthracycline (doxorubicin) + cyclophosphamide followed by paclitaxel + trastuzumab + pertuzumab (ddAC-PacHP) in patients with early HER2-positive breast cancer (T2-4, N1-3, M0).

Protection of trial subjects

All study subjects were required to read and sign and Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

11 Jan 2019

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

36 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Brazil: 75

Country: Number of subjects enrolled

Canada: 26

Country: Number of subjects enrolled

Germany: 33

Country: Number of subjects enrolled

Italy: 46

Country: Number of subjects enrolled

Japan: 39

Country: Number of subjects enrolled

Korea, Republic of: 33

Country: Number of subjects enrolled

Poland: 31

Country: Number of subjects enrolled

Russian Federation: 45

Country: Number of subjects enrolled

Spain: 59

Country: Number of subjects enrolled

Taiwan: 49

Country: Number of subjects enrolled

United States: 8

Country: Number of subjects enrolled

Czechia: 10

Worldwide total number of subjects

454

EEA total number of subjects

179

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)

411

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

The study was conducted at 74 centers in 12 countries.

Screening details

A total of 669 participants were screened, of which a total of 454 participants were enrolled.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind ^[1]

Roles blinded

Subject, Carer

Are arms mutually exclusive

Yes

Atezolizumab +ddAC-PacHP

Arm description

Participants received atezolizumab (atezo) 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2 IV), followed by atezo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8mg/kg IV loading dose) Q3W for 4 cycles, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants continued to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant and adjuvant setting: atezo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who did not achieve pCR had option of receiving blinded atezo+trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL dated 3 Feb 2021 treatment with atezo was discontinued.

Arm type

Experimental

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Atezolizumab was administered by intravenous infusion at a dose of 840 milligrams (mg) every 2 weeks (Q2W) for 4 cycles during neoadjuvant phase followed by atezolizumab 1200 mg IV every 3 weeks (Q3W) for 4 cycles. During the adjuvant phase, participants continued to receive atezolizumab 1200 mg IV Q3W. In response to USM DIL dated 3 Feb 2021 treatment with atezolizumab must be discontinued.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin was administered by IV infusion in the neoadjuvant setting at a dosage of 60 mg/m^2 on Day 2 of a 14 day cycle for cylces 1-4.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide was administered by IV infusion in the neoadjuvant setting at a dosage of 600 mg/m^2 on Day 2 of a 14 day cycle for cylces 1-4.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered by IV infusion in the neoadjuvant setting at a dosage of 80 mg/m^2 for 12 continuous weeks (cycles 5-8).

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Herceptin

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab was administered on Day 1 of a 21-day cycle as an 8-mg/kilogram(kg) loading dose and then a 6 mg/kg IV Q3W up to 52 weeks.

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

Other name

Perjeta

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pertuzumab was administered on Day 1 of a 21-day cycle as a fixed non-weight-based dose of 840-mg IV loading dose and then 420 mg IV Q3W up to 52 weeks.

Investigational medicinal product name

Trastuzumab Emtansine

Investigational medicinal product code

Other name

Kadcyla

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab emtansine was administered at a dose of 3.6 mg/kg IV infusion Q3W.

Placebo + ddAC-PacHP

Arm description

Participants received placebo 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2 IV), followed by placebo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W for 4 cycles & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants continued to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant & adjuvant setting: placebo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who did not achieve pCR had option of receiving blinded atezolizumab + trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL, dated 3 Feb 2021 treatment with placebo was discontinued.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Placebo was administered by intravenous infusion at a dose of 840 mg Q2W for 4 cycles during neoadjuvant phase followed by placebo 1200 mg IV Q3W for 4 cycles. During the adjuvant phase, participants continued to receive placebo 1200 mg IV Q3W. In response to USM DIL dated 3 Feb 2021 treatment with placebo must be discontinued.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide was administered by IV infusion in the neoadjuvant setting at a dosage of 600 mg/m^2 on Day 2 of a 14 day cycle for cylces 1-4.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin was administered by IV infusion in the neoadjuvant setting at a dosage of 60 mg/m^2 on Day 2 of a 14 day cycle for cylces 1-4.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered by IV infusion in the neoadjuvant setting at a dosage of 80 mg/m^2 for 12 continuous weeks (cycles 5-8).

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Herceptin

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab was administered on Day 1 of a 21-day cycle as an 8-mg/kg loading dose and then a 6 mg/kg IV Q3W up to 52 weeks.

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

Other name

Perjeta

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pertuzumab was administered on Day 1 of a 21-day cycle as a fixed non-weight-based dose of 840-mg IV loading dose and then 420 mg IV Q3W up to 52 weeks.

Investigational medicinal product name

Trastuzumab Emtansine

Investigational medicinal product code

Other name

Kadcyla

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab emtansine was administered at a dose of 3.6 mg/kg IV infusion Q3W.

Notes
[1] - The roles blinded appear to be inconsistent with a double blind trial.
Justification: The roles blinded are correct

Number of subjects in period 1	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Started	226	228
Completed	0	0
Not completed	226	228
Consent withdrawn by subject	5	5
Physician decision	-	2
Continuing on Study	215	215
Death	6	4
TSH result is unstable	-	1
Protocol deviation	-	1

Baseline characteristics

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Reporting group title

Atezolizumab +ddAC-PacHP

Reporting group description

Reporting group title

Placebo + ddAC-PacHP

Reporting group description

Reporting group values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP	Total
Number of subjects	226	228	454
Age Categorical
Units: Participants
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	204	207	411
From 65-84 years	22	21	43
85 years and over	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	50.3 ( 10.7 )	50.8 ( 10.4 )	-
Sex: Female, Male
Units: Participants
Male	1	1	2
Female	225	227	452
Race
Units: Subjects
American Indian or Alaska Native	1	1	2
Asian	62	66	128
Black or African American	8	13	21
White	149	142	291
Multiple	2	3	5
Unknown	4	3	7
Ethnicity
Units: Subjects
Hispanic or Latino	26	33	59
Not Hispanic or Latino	195	191	386
Not Reported	5	4	9

End points

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Reporting group title

Atezolizumab +ddAC-PacHP

Reporting group description

Reporting group title

Placebo + ddAC-PacHP

Reporting group description

Primary: Percentage of Participants with Pathological Complete Response (pCR) in the PD-L1-Positive Population (IC 1/2/3)

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End point title

Percentage of Participants with Pathological Complete Response (pCR) in the PD-L1-Positive Population (IC 1/2/3)

End point description

pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging system, 8th edition). The PD-L1-positive population is defined as participants in the Intent-to-Treat (ITT) population whose PD-L1 status is IC1/2/3 at the time of randomization.

End point type

Primary

End point timeframe

From randomization to approximately 6 months

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	109	109
Units: Percentage of Particpants
number (not applicable)	64.2	72.5

Atezolizumab +ddAC-PacHP vs. Placebo + ddAC-PacHP

Statistical analysis description

Treatment comparison was made using Cochran-Mantel-Haenszel test stratified by disease stage (T2 vs. T3-4) and hormone receptor status (estrogen receptor (ER) positive and/or progesterone receptor (PgR) positive vs. ER negative and PgR negative).

Comparison groups

Atezolizumab +ddAC-PacHP v Placebo + ddAC-PacHP

Number of subjects included in analysis

218

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1846 ^[1]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.37

upper limit

1.21

Notes
[1] - The threshold for statistical significance was a p-value =0.048

Primary: pCR in the ITT Population

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End point title

pCR in the ITT Population

End point description

pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging system, 8th edition). The ITT population is defined as all randomized participants, regardless of whether the assigned study treatment was received.

End point type

Primary

End point timeframe

From randomization to approximately 6 months

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	226	228
Units: Percentage of Participants
number (not applicable)	62.4	62.7

Atezolizumab +ddAC-PacHP vs. Placebo + ddAC-PacHP

Statistical analysis description

Treatment comparison was made using Cochran-Mantel-Haenszel test stratified by disease stage (T2 vs. T3-4) and hormone receptor status (ER positive and/or PgR positive vs. ER negative and PgR negative).

Comparison groups

Atezolizumab +ddAC-PacHP v Placebo + ddAC-PacHP

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9551 ^[2]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

1.46

Notes
[2] - The threshold for statistical significance was a p-value =0.002

Secondary: Percentage of Participants with pCR Based on Hormone Receptor Status

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End point title

Percentage of Participants with pCR Based on Hormone Receptor Status

End point description

pCR (ypT0/is ypN0) based upon hormone receptor status (estrogen receptor [ER]/progesterone receptor [PgR] positive or ER/PgR negative). The ITT population is defined as all randomized participants, regardless of whether the assigned study treatment was received.

End point type

Secondary

End point timeframe

From randomization to approximately 24 months.

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	226	228
Units: Percentage of Participants
number (not applicable)
ER+ and/or PgR+ (n= 116, 117)	50.9	54.7
ER- and/or PgR- (n= 110, 111)	74.5	71.2

No statistical analyses for this end point

Secondary: Percentage of Participants with pCR in the PD-L1-Negative Population

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End point title

Percentage of Participants with pCR in the PD-L1-Negative Population

End point description

pCR (ypT0/is ypN0) in the IC 0 Population. The PD-L1-negative population is defined as participants in the ITT population whose PD-L1 status is IC 0 at the time of randomization.

End point type

Secondary

End point timeframe

From randomization to approximately 24 months

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	117	119
Units: Percentage of Participants
number (not applicable)	60.7	53.8

No statistical analyses for this end point

Secondary: Event-Free Survival (EFS)

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End point title

Event-Free Survival (EFS)

End point description

EFS defined as the time from randomization to the first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause, whichever occurs first, in all patients and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3). The ITT population is defined as all randomized participants, regardless of whether the assigned study treatment was received. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.

End point type

Secondary

End point timeframe

From randomization to first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause (up to approximately 54 months)

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	0 ^[3]	0 ^[4]
Units: Months
median (confidence interval 95%)	( to )	( to )

Notes
[3] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
[4] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion

No statistical analyses for this end point

Secondary: Disease-Free Survival (DFS)

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End point title

Disease-Free Survival (DFS)

End point description

DFS defined as the time from surgery to the first documented disease recurrence or death from any cause, whichever occurs first, in all patients who undergo surgery and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3). The ITT population is defined as all randomized participants, regardless of whether the assigned study treatment was received. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.

End point type

Secondary

End point timeframe

Time from surgery to first documented disease recurrence or death from any cause (up to approximately 54 months)

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	0 ^[5]	0 ^[6]
Units: Months
median (confidence interval 95%)	( to )	( to )

Notes
[5] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
[6] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS defined as the time from randomization to death from any cause in all patients and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3). The ITT population is defined as all randomized participants, regardless of whether the assigned study treatment was received. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.

End point type

Secondary

End point timeframe

From randomization to date of death from any cause (up to approximately 54 months)

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	0 ^[7]	0 ^[8]
Units: Months
median (confidence interval 95%)	( to )	( to )

Notes
[7] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
[8] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion

No statistical analyses for this end point

Secondary: Mean Changes From Baseline in Function (Role, Physical)

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End point title

Mean Changes From Baseline in Function (Role, Physical)

End point description

EORTC QLQ-C30 is a self-reported questionnaire that included functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), global health scale/quality of life (GHS/QOL) and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Questions 1-28 on the QLQ-C30 were on a 4-point scale (1=Not at All to 4=Very Much). Questions 29-30 (GHS scale) were on a 7-point scale (1=Very Poor to 7=Excellent). For this instrument, GHS/QOL and functional scales were linearly transformed so each score ranged 0-100, where lower scores indicate poorer functioning (e.g., worsening) and higher scores indicate better functioning (e.g., improvement). The patient-reported outcomes (PRO)-evaluable population is defined as participants in the ITT population with a baseline and at least 1 post-baseline PRO assessment. 9999999 = SD was non-estimable as only 1 participant was evaluated for this category.

End point type

Secondary

End point timeframe

Baseline; Day 1 of Cycle 1-9, on Day 1 of every other cycle thereafter until Cycle 22; at the treatment discontinuation or early termination visit and follow up visit. Cycle 1-4, each cycle is 14 days. Cycle 5-22, each cycle is 21 days.

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	223	224
Units: Units on a scale
arithmetic mean (standard deviation)
Role: Baseline (n=223, 224)	91.70 ( 16.28 )	90.85 ( 20.26 )
Role: Cycle (C) 2 Day (D) 1 (n=222, 222)	-13.06 ( 23.02 )	-9.83 ( 23.08 )
Role: C3D1 (n=219, 220)	-17.88 ( 26.20 )	-15.15 ( 22.64 )
Role: C4D1 (n=217, 216)	-22.27 ( 27.04 )	-17.98 ( 25.10 )
Role: C5D1 (n=218, 219)	-24.08 ( 28.21 )	-19.79 ( 26.36 )
Role: C6D1 (n=215, 216)	-20.70 ( 25.46 )	-18.60 ( 25.01 )
Role: C7D1 (n=210, 210)	-19.21 ( 25.50 )	-16.67 ( 26.34 )
Role: C8D1 (n=211, 208)	-21.25 ( 26.48 )	-17.79 ( 26.39 )
Role: Adjuvant Week 1 D1 (n=206, 202)	-22.82 ( 26.70 )	-26.24 ( 31.27 )
Role: Adjuvant Week 7 D43 (n=183, 176)	-15.48 ( 22.31 )	-15.15 ( 26.50 )
Role: Adjuvant Week 13 D85 (n=171, 163)	-14.42 ( 23.77 )	-15.24 ( 26.99 )
Role: Adjuvant Week 19 D127 (n=155, 147)	-14.30 ( 24.26 )	-15.42 ( 25.74 )
Role: Adjuvant Week 25 D169 (n=134, 127)	-13.68 ( 24.00 )	-15.88 ( 22.99 )
Role: Adjuvant Week 31 D211 (n=112, 110)	-13.24 ( 23.69 )	-14.55 ( 24.43 )
Role: Adjuvant Week 37 D253 (n=91, 94)	-9.34 ( 21.11 )	-15.43 ( 27.35 )
Role: End of Treatment (EOT) (n=108, 116)	-14.04 ( 25.18 )	-18.10 ( 29.04 )
Role: Follow-Up (FU) 1 D1 (n=62, 68)	-11.02 ( 25.06 )	-17.16 ( 23.21 )
Role: FU2D92 (n=20, 33)	-9.17 ( 23.24 )	-14.65 ( 25.94 )
Role: FU3D183 (n=3, 8)	-16.67 ( 16.67 )	-10.42 ( 21.71 )
Role: FU4D274 (n=3, 6)	-27.78 ( 25.46 )	-25.00 ( 9.13 )
Role: FU5D457 (n=0, 1)	0.0 ( 0.0 )	-33.33 ( 9999999 )
Physical: Baseline (n=223, 224)	92.74 ( 11.60 )	92.20 ( 12.92 )
Physical: C2D1 (n=222, 221)	-4.32 ( 9.75 )	-3.88 ( 13.44 )
Physical: C3D1 (n=219, 220)	-6.82 ( 13.39 )	-7.18 ( 12.91 )
Physical: C4D1 (n=217, 216)	-11.98 ( 17.67 )	-9.48 ( 14.65 )
Physical: C5D1 (n=218, 219)	-12.84 ( 18.19 )	-10.67 ( 15.91 )
Physical: C6D1 (n=215, 216)	-12.25 ( 15.97 )	-11.40 ( 17.05 )
Physical: C7D1 (n=210, 210)	-11.33 ( 14.86 )	-11.45 ( 17.43 )
Physical: C8D1 (n=211, 208)	-13.30 ( 17.11 )	-11.56 ( 17.54 )
Physical: Adjuvant Week 1 D1 (n=206, 202)	-12.27 ( 18.26 )	-12.19 ( 19.27 )
Physical: Adjuvant Week 7 D43 (n=183, 176)	-8.96 ( 14.74 )	-8.60 ( 16.33 )
Physical: Adjuvant Week 13 D85 (n=171, 163)	-8.38 ( 14.97 )	-8.88 ( 15.04 )
Physical: Adjuvant Week 19 D127 (n=154, 147)	-9.22 ( 15.17 )	-10.03 ( 15.52 )
Physical: Adjuvant Week 25 D169 (n=134, 127)	-9.35 ( 16.19 )	-8.45 ( 14.34 )
Physical: Adjuvant Week 31 D211 (n=112, 110)	-7.80 ( 13.69 )	-9.88 ( 15.84 )
Physical: Adjuvant Week 37 D253 (n=91, 94)	-7.77 ( 13.67 )	-10.78 ( 16.82 )
EOT (n=109, 116)	-8.20 ( 15.78 )	-13.05 ( 19.17 )
Physical: FU1D1 (n=62, 68)	-8.06 ( 18.11 )	-11.57 ( 19.29 )
Physical: FU2D92 (n=20, 33)	-3.33 ( 12.52 )	-9.90 ( 15.73 )
Physical: FU3D183 (n=3, 8)	2.22 ( 16.78 )	-14.17 ( 7.51 )
Physical: FU4D274 (n=3, 6)	0.00 ( 20.00 )	-6.67 ( 11.93 )
Physical: FU5D457 (n=0, 1)	0.0 ( 0.0 )	60.00 ( 9999999 )

No statistical analyses for this end point

Secondary: Mean Changes From Baseline in Global Health Status

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End point title

Mean Changes From Baseline in Global Health Status

End point description

EORTC QLQ-C30 is a self-reported questionnaire that included functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), GHS/QOL and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Questions 1-28 on the QLQ-C30 were on a 4-point scale (1=Not at All to 4=Very Much). Questions 29-30 (GHS scale) were on a 7-point scale (1=Very Poor to 7=Excellent). For this instrument, GHS/QOL and functional scales were linearly transformed so each score ranged 0-100, where lower scores indicate poorer functioning (e.g., worsening) and higher scores indicate better functioning (e.g., improvement). The PRO-evaluable population is defined as participants in the ITT population with a baseline and at least 1 post-baseline PRO assessment. 9999999 = SD was non-estimable as only 1 participant was evaluated for this category.

End point type

Secondary

End point timeframe

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	223	224
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (n=223, 224)	76.49 ( 19.33 )	76.79 ( 19.05 )
C2D1 (n=222, 222)	-7.28 ( 19.70 )	-6.31 ( 19.54 )
C3D1 (n=219, 220)	-10.96 ( 22.16 )	-8.33 ( 20.93 )
C4D1 (n=217, 216)	-13.67 ( 22.47 )	-10.88 ( 21.51 )
C5D1 (n=218, 219)	-14.14 ( 23.76 )	-12.63 ( 23.66 )
C6D1 (n=215, 216)	-12.33 ( 22.10 )	-9.99 ( 20.96 )
C7D1 (n=210, 210)	-11.47 ( 19.81 )	-10.52 ( 21.59 )
C8D1 (n=211, 208)	-12.72 ( 22.45 )	-10.86 ( 22.66 )
Adjuvant Week 1 D1 (n=206, 202)	-7.89 ( 21.89 )	-7.14 ( 23.68 )
Adjuvant Week 7 D43 (n=183, 176)	-7.51 ( 22.97 )	-5.21 ( 21.96 )
Adjuvant Week 13 D85 (n=171, 163)	-7.07 ( 22.31 )	-6.75 ( 21.13 )
Adjuvant Week 19 D127 (n=155, 147)	-7.20 ( 21.47 )	-6.01 ( 20.52 )
Adjuvant Week 25 D169 (n=134, 127)	-8.02 ( 21.10 )	-5.05 ( 20.39 )
Adjuvant Week 31 D211 (n=112, 110)	-7.29 ( 21.75 )	-7.80 ( 22.56 )
Adjuvant Week 37 D253 (n=91, 94)	-5.95 ( 21.71 )	-6.03 ( 20.72 )
EOT (n=109, 116)	-5.96 ( 22.08 )	-9.41 ( 24.29 )
FU1D1 (n=62, 68)	-3.90 ( 21.64 )	-5.15 ( 21.01 )
FU2D92 (n=20, 33)	-1.25 ( 19.55 )	-3.03 ( 16.11 )
FU3D183 (n=3, 8)	-8.33 ( 8.33 )	-7.29 ( 15.06 )
FU4D274 (n=3, 6)	-13.89 ( 12.73 )	-31.94 ( 37.42 )
FU5D457 (n=0, 1)	0.0 ( 0.0 )	-16.67 ( 9999999 )

No statistical analyses for this end point

Secondary: Percentage of Participants With Adverse Events

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End point title

Percentage of Participants With Adverse Events

End point description

The safety-evaluable population is defined as participants who received at least one dose of any study drug.

End point type

Secondary

End point timeframe

From randomization up until clinical cut-off date (approximately 24 months)

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	226	225
Units: Percentage of Participants
number (not applicable)	100	100

No statistical analyses for this end point

Secondary: Maximum Serum Concentration (Cmax) of Atezolizumab

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End point title

Maximum Serum Concentration (Cmax) of Atezolizumab ^[9]

End point description

Cmax is the maximum (or peak) concentration that a study drug achieves in the body. The pharmacokinetic (PK)-evaluable population is defined as all participants who received any dose of study medication and who have at least one post-baseline PK sample available.

End point type

Secondary

End point timeframe

30 minutes post infusion on Day 1 Cycle (C) 1.

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analyses for this end point. Atezolizumab was not administered in the placebo arm.

End point values	Atezolizumab +ddAC-PacHP
Number of subjects analysed	219
Units: micrograms/milliliters (ug/mL)
arithmetic mean (standard deviation)	348 ( 122 )

No statistical analyses for this end point

Secondary: Minimum Serum Concentration (Cmin) of Atezolizumab

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End point title

Minimum Serum Concentration (Cmin) of Atezolizumab ^[10]

End point description

End point type

Secondary

End point timeframe

Pre-dose on Day 1 Cycle (C) 2, 3, 4, 8, 12, 16, ATDV (an average of 1 year). C 2-4, each C is 14 days. C 8-16, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analyses for this end point. Atezolizumab was not administered in the placebo arm.

End point values	Atezolizumab +ddAC-PacHP
Number of subjects analysed	226
Units: ug/mL
arithmetic mean (standard deviation)
C2D1/predose (n=222)	103 ( 40.3 )
C3D1/predose (n=214)	163 ( 44.4 )
C4D1/predose (n=212)	204 ( 51.9 )
C8D1/predose (n=203)	225 ( 97.1 )
C12D1/predose (n=166)	217 ( 101 )
C16D1/predose (n=133)	226 ( 114 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) for Pertuzumab and Trastuzumab in Serum

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End point title

Trough Concentration (Ctrough) for Pertuzumab and Trastuzumab in Serum

End point description

The PK-evaluable population is defined as all participants who received any dose of study medication and who have at least one post-baseline PK sample available.

End point type

Secondary

End point timeframe

Pre-dose on Day 1 Cycle (C) 8, 12, and at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-12, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	226	225
Units: ug/mL
arithmetic mean (standard deviation)
Pertuzumab: C8D1/predose (n=205, 201)	93.2 ( 40.7 )	94.8 ( 39.8 )
Pertuzumab: C12D1/predose (n=150, 147)	87.7 ( 58.4 )	91.6 ( 59.7 )
Trastuzumab: C8D1/predose (n=205, 201)	58.5 ( 29.1 )	56.5 ( 23.9 )
Trastuzumab: C12D1/predose (n=150, 147)	62.4 ( 32.7 )	60.4 ( 30.9 )

No statistical analyses for this end point

Secondary: Cmin of Trastuzumab Emtansine in Serum

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End point title

Cmin of Trastuzumab Emtansine in Serum

End point description

Cmin is the minimum (or trough) concentration that a study drug achieves in the body. The PK-evaluable population is defined as all participants who received any dose of study medication and who have at least one post-baseline PK sample available. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.

End point type

Secondary

End point timeframe

Pre-dosDay 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit (an average of 1 year). Cycle 9 and 12 are each 21 days. With protocol version 5, collection is only required at the time of treatment discontinuation/completion (an average of 1 year

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	0 ^[11]	0 ^[12]
Units: ug/mL
arithmetic mean (standard deviation)	( )	( )

Notes
[11] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
[12] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion

No statistical analyses for this end point

Secondary: Cmax of Trastuzumab Emtansine in Serum

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End point title

Cmax of Trastuzumab Emtansine in Serum

End point description

Cmax is the maximum (or peak) concentration that a study drug achieves in the body. The PK-evaluable population is defined as all participants who received any dose of study medication and who have at least one post-baseline PK sample available. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.

End point type

Secondary

End point timeframe

Day 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit (an average of 1 year). Cycle 9 and 12 are each 21 days. With protocol version 5, collection is only required at the time of treatment discontinuation/completion (an average of 1 year).

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	0 ^[13]	0 ^[14]
Units: ug/mL
arithmetic mean (standard deviation)	( )	( )

Notes
[13] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
[14] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion

No statistical analyses for this end point

Secondary: Number of Participants with Treatment-Emergent Anti-Drug Antibodies (ADAs) to Atezolizumab

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End point title

Number of Participants with Treatment-Emergent Anti-Drug Antibodies (ADAs) to Atezolizumab ^[15]

End point description

Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected). The immunogenicity analysis included all safety evealuable participants who had at least one baseline or post-baseline ADA result from at least one sample.

End point type

Secondary

End point timeframe

Day 1 Cycle (C) 1, 2, 3, 4, 8, 12, 16, at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-16, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analyses for this end point. Atezolizumab was not administered in the placebo arm.

End point values	Atezolizumab +ddAC-PacHP
Number of subjects analysed	225
Units: Participants
number (not applicable)
Baseline (BL): ADA Positive	1
BL: ADA Negative	224
Post-BL: Treatment-Emergent ADA Positive	7
Post-BL: Treatment-Emergent ADA Negative	218

No statistical analyses for this end point

Secondary: Number of Participants with Treatment-Emergent ADAs to Trastuzumab

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End point title

Number of Participants with Treatment-Emergent ADAs to Trastuzumab

End point description

End point type

Secondary

End point timeframe

Day 1 Cycle (C) 1, 8, 12 and at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-12, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	225	225
Units: Participants
number (not applicable)
BL: ADA Positive (n=220, 211)	2	1
BL: ADA Negative (220, 211)	218	210
Post-BL: Trt.-Emergent ADA Positive (n=216, 214)	1	0
Post-BL: Trt.-Emergent ADA Negative (n=216, 214)	215	214

No statistical analyses for this end point

Secondary: Number of Participants with Treatment-Emergent ADAs to Pertuzumab

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End point title

Number of Participants with Treatment-Emergent ADAs to Pertuzumab

End point description

End point type

Secondary

End point timeframe

Day 1 of Cycle (C) 1, 8, 12, and at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-12, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	225	225
Units: Participants
number (not applicable)
BL: ADA Positive (n=221, 211)	6	3
BL: ADA Negative (n=221, 211)	215	208
Post-BL: Trt-Emergent ADA Positive (n=216, 214)	13	12
Post-BL: Trt-Emergent ADA Negative (n=216, 214)	203	202

No statistical analyses for this end point

Secondary: Percentage of Particpants with pCR Based on PIK3CA Mutation Status

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End point title

Percentage of Particpants with pCR Based on PIK3CA Mutation Status

End point description

pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging system, 8th edition). The ITT population is defined as all randomized participants, regardless of whether the assigned study treatment was received.

End point type

Secondary

End point timeframe

From randomization to approximately 24 months

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	226	228
Units: Percentage of participants with pCR
number (not applicable)
Mutated (n pCR=40, 34)	59.7	55.7
Wildtype (n pCR=98, 101)	65.3	65.2
Missing (n pCR=3, 8)	33.3	66.7

No statistical analyses for this end point

Secondary: Number of Participants with Treatment-Emergent ADAs to Trastuzumab Emtansine

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End point title

Number of Participants with Treatment-Emergent ADAs to Trastuzumab Emtansine

End point description

Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected). Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.

End point type

Secondary

End point timeframe

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	0 ^[16]	0 ^[17]
Units: Participants
number (not applicable)

Notes
[16] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
[17] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion

No statistical analyses for this end point

Secondary: EFS Based on PIK3CA Mutation Status

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End point title

EFS Based on PIK3CA Mutation Status

End point description

Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.

End point type

Secondary

End point timeframe

From randomization to first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause (up to approximately 54 months)

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	0 ^[18]	0 ^[19]
Units: Months
median (confidence interval 95%)	( to )	( to )

Notes
[18] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
[19] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion

No statistical analyses for this end point

Secondary: DFS Based on PIK3CA Mutation Status

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End point title

DFS Based on PIK3CA Mutation Status

End point description

Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.

End point type

Secondary

End point timeframe

Time from surgery to first documented disease recurrence or death from any cause (up to approximately 54 months)

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	0 ^[20]	0 ^[21]
Units: Months
median (confidence interval 95%)	( to )	( to )

Notes
[20] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
[21] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion

No statistical analyses for this end point

Secondary: OS Based on PIK3CA Mutation Status

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End point title

OS Based on PIK3CA Mutation Status

End point description

Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.

End point type

Secondary

End point timeframe

From randomization to date of death from any cause (up to approximately 54 months)

End point values	Atezolizumab +ddAC-PacHP	Placebo + ddAC-PacHP
Number of subjects analysed	0 ^[22]	0 ^[23]
Units: Months
median (confidence interval 95%)	( to )	( to )

Notes
[22] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion
[23] - Data collection is ongoing and the results will be disclosed within 1 year from Study Completion

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up until clinical cut off date (approximately 24 months)

Adverse event reporting additional description

AEs were recorded for the safety-evaluable population which included all randomized participants who received any dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Placebo + ddAC-PacHP

Reporting group description

Reporting group title

Atezolizumab +ddAC-PacHP

Reporting group description

Serious adverse events	Placebo + ddAC-PacHP	Atezolizumab +ddAC-PacHP
Total subjects affected by serious adverse events
subjects affected / exposed	44 / 225 (19.56%)	62 / 226 (27.43%)
number of deaths (all causes)	4	6
number of deaths resulting from adverse events	0	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MENINGIOMA
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NERVOUS SYSTEM NEOPLASM BENIGN
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
SUBCLAVIAN VEIN THROMBOSIS
subjects affected / exposed	0 / 225 (0.00%)	2 / 226 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
DEEP VEIN THROMBOSIS
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
THROMBOSIS
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
VASCULAR PAIN
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
JUGULAR VEIN THROMBOSIS
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
PYREXIA
subjects affected / exposed	3 / 225 (1.33%)	3 / 226 (1.33%)
occurrences causally related to treatment / all	1 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
FATIGUE
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ASTHENIA
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CAPSULAR CONTRACTURE ASSOCIATED WITH BREAST IMPLANT
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
ADNEXAL TORSION
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
DYSPNOEA EXERTIONAL
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INTERSTITIAL LUNG DISEASE
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ALVEOLITIS
subjects affected / exposed	1 / 225 (0.44%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
IMMUNE-MEDIATED PNEUMONITIS
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PLEURAL EFFUSION
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONITIS
subjects affected / exposed	2 / 225 (0.89%)	9 / 226 (3.98%)
occurrences causally related to treatment / all	2 / 2	9 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
ACUTE RESPIRATORY DISTRESS SYNDROME
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	3 / 225 (1.33%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	2 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
DEPRESSION
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
DEVICE EXTRUSION
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
GAMMA-GLUTAMYLTRANSFERASE INCREASED
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GLYCOSYLATED HAEMOGLOBIN INCREASED
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PLATELET COUNT DECREASED
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LIPASE INCREASED
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
TRANSAMINASES INCREASED
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
EJECTION FRACTION DECREASED
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
OXYGEN SATURATION DECREASED
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
IMPLANTATION COMPLICATION
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
WOUND COMPLICATION
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SEROMA
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LUMBAR VERTEBRAL FRACTURE
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
RADIATION PNEUMONITIS
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INFUSION RELATED REACTION
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
ATRIAL TACHYCARDIA
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC FAILURE CHRONIC
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MITRAL VALVE INCOMPETENCE
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC FAILURE ACUTE
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ATRIAL FIBRILLATION
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC FAILURE CONGESTIVE
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC FAILURE
subjects affected / exposed	5 / 225 (2.22%)	3 / 226 (1.33%)
occurrences causally related to treatment / all	6 / 6	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
MENINGITIS NONINFECTIVE
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
NEUTROPENIA
subjects affected / exposed	2 / 225 (0.89%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ANAEMIA
subjects affected / exposed	1 / 225 (0.44%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	3 / 225 (1.33%)	10 / 226 (4.42%)
occurrences causally related to treatment / all	3 / 3	11 / 12
deaths causally related to treatment / all	0 / 0	0 / 0
LEUKOPENIA
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
APLASTIC ANAEMIA
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
MEIBOMIANITIS
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
EYE DISCHARGE
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
COLITIS
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	1 / 225 (0.44%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
IMMUNE-MEDIATED PANCREATITIS
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NAUSEA
subjects affected / exposed	1 / 225 (0.44%)	2 / 226 (0.88%)
occurrences causally related to treatment / all	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
STOMATITIS
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PANCREATITIS
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
HEPATIC HAEMORRHAGE
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
STEATOHEPATITIS
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERTRANSAMINASAEMIA
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
BILIARY COLIC
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
ACUTE KIDNEY INJURY
subjects affected / exposed	1 / 225 (0.44%)	2 / 226 (0.88%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
SECONDARY ADRENOCORTICAL INSUFFICIENCY
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ADRENAL INSUFFICIENCY
subjects affected / exposed	0 / 225 (0.00%)	4 / 226 (1.77%)
occurrences causally related to treatment / all	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOPHYSITIS
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOTHYROIDISM
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
POST PROCEDURAL INFECTION
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INFLUENZA
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMOCYSTIS JIROVECII PNEUMONIA
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
VULVAL CELLULITIS
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
VASCULAR ACCESS SITE INFECTION
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19
subjects affected / exposed	1 / 225 (0.44%)	2 / 226 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
ABSCESS
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BACTERAEMIA
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
FEBRILE INFECTION
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
APPENDICITIS
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MASTITIS
subjects affected / exposed	0 / 225 (0.00%)	2 / 226 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	0 / 225 (0.00%)	2 / 226 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONIA BACTERIAL
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HERPES ZOSTER
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ANAL ABSCESS
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	2 / 225 (0.89%)	2 / 226 (0.88%)
occurrences causally related to treatment / all	2 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	2 / 225 (0.89%)	4 / 226 (1.77%)
occurrences causally related to treatment / all	1 / 2	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
STAPHYLOCOCCAL BACTERAEMIA
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
POSTOPERATIVE WOUND INFECTION
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DEVICE RELATED INFECTION
subjects affected / exposed	0 / 225 (0.00%)	2 / 226 (0.88%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
CYSTITIS
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SEPTIC SHOCK
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
STAPHYLOCOCCAL INFECTION
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTRITIS BACTERIAL
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
TOOTH ABSCESS
subjects affected / exposed	1 / 225 (0.44%)	0 / 226 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
WOUND INFECTION
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
METABOLIC ACIDOSIS
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERGLYCAEMIA
subjects affected / exposed	0 / 225 (0.00%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DIABETES MELLITUS
subjects affected / exposed	1 / 225 (0.44%)	1 / 226 (0.44%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Placebo + ddAC-PacHP	Atezolizumab +ddAC-PacHP
Total subjects affected by non serious adverse events
subjects affected / exposed	225 / 225 (100.00%)	226 / 226 (100.00%)
Vascular disorders
HOT FLUSH
subjects affected / exposed	25 / 225 (11.11%)	23 / 226 (10.18%)
occurrences all number	28	27
HYPERTENSION
subjects affected / exposed	13 / 225 (5.78%)	14 / 226 (6.19%)
occurrences all number	21	23
General disorders and administration site conditions
CHILLS
subjects affected / exposed	13 / 225 (5.78%)	8 / 226 (3.54%)
occurrences all number	14	8
PYREXIA
subjects affected / exposed	42 / 225 (18.67%)	44 / 226 (19.47%)
occurrences all number	66	60
PAIN
subjects affected / exposed	15 / 225 (6.67%)	15 / 226 (6.64%)
occurrences all number	21	20
FATIGUE
subjects affected / exposed	38 / 225 (16.89%)	61 / 226 (26.99%)
occurrences all number	49	104
ASTHENIA
subjects affected / exposed	85 / 225 (37.78%)	96 / 226 (42.48%)
occurrences all number	189	197
MUCOSAL INFLAMMATION
subjects affected / exposed	29 / 225 (12.89%)	33 / 226 (14.60%)
occurrences all number	43	41
MALAISE
subjects affected / exposed	16 / 225 (7.11%)	11 / 226 (4.87%)
occurrences all number	21	20
OEDEMA PERIPHERAL
subjects affected / exposed	16 / 225 (7.11%)	14 / 226 (6.19%)
occurrences all number	17	19
Reproductive system and breast disorders
BREAST PAIN
subjects affected / exposed	15 / 225 (6.67%)	8 / 226 (3.54%)
occurrences all number	16	8
Respiratory, thoracic and mediastinal disorders
RHINORRHOEA
subjects affected / exposed	13 / 225 (5.78%)	24 / 226 (10.62%)
occurrences all number	17	28
DYSPNOEA
subjects affected / exposed	22 / 225 (9.78%)	18 / 226 (7.96%)
occurrences all number	30	21
EPISTAXIS
subjects affected / exposed	28 / 225 (12.44%)	28 / 226 (12.39%)
occurrences all number	37	30
OROPHARYNGEAL PAIN
subjects affected / exposed	13 / 225 (5.78%)	12 / 226 (5.31%)
occurrences all number	14	13
COUGH
subjects affected / exposed	46 / 225 (20.44%)	37 / 226 (16.37%)
occurrences all number	62	47
Psychiatric disorders
INSOMNIA
subjects affected / exposed	29 / 225 (12.89%)	38 / 226 (16.81%)
occurrences all number	34	46
ANXIETY
subjects affected / exposed	15 / 225 (6.67%)	8 / 226 (3.54%)
occurrences all number	17	8
Investigations
BLOOD LACTATE DEHYDROGENASE INCREASED
subjects affected / exposed	9 / 225 (4.00%)	12 / 226 (5.31%)
occurrences all number	9	13
LYMPHOCYTE COUNT DECREASED
subjects affected / exposed	12 / 225 (5.33%)	13 / 226 (5.75%)
occurrences all number	19	21
PLATELET COUNT DECREASED
subjects affected / exposed	12 / 225 (5.33%)	15 / 226 (6.64%)
occurrences all number	16	19
NEUTROPHIL COUNT DECREASED
subjects affected / exposed	29 / 225 (12.89%)	33 / 226 (14.60%)
occurrences all number	47	69
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	49 / 225 (21.78%)	65 / 226 (28.76%)
occurrences all number	77	99
BLOOD ALKALINE PHOSPHATASE INCREASED
subjects affected / exposed	12 / 225 (5.33%)	10 / 226 (4.42%)
occurrences all number	12	12
EJECTION FRACTION DECREASED
subjects affected / exposed	19 / 225 (8.44%)	14 / 226 (6.19%)
occurrences all number	25	14
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed	10 / 225 (4.44%)	13 / 226 (5.75%)
occurrences all number	16	25
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	63 / 225 (28.00%)	77 / 226 (34.07%)
occurrences all number	93	126
WEIGHT DECREASED
subjects affected / exposed	14 / 225 (6.22%)	24 / 226 (10.62%)
occurrences all number	14	25
Injury, poisoning and procedural complications
WOUND COMPLICATION
subjects affected / exposed	16 / 225 (7.11%)	13 / 226 (5.75%)
occurrences all number	16	14
RADIATION SKIN INJURY
subjects affected / exposed	40 / 225 (17.78%)	51 / 226 (22.57%)
occurrences all number	41	53
INFUSION RELATED REACTION
subjects affected / exposed	33 / 225 (14.67%)	39 / 226 (17.26%)
occurrences all number	41	58
PROCEDURAL PAIN
subjects affected / exposed	18 / 225 (8.00%)	15 / 226 (6.64%)
occurrences all number	18	15
Nervous system disorders
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed	38 / 225 (16.89%)	46 / 226 (20.35%)
occurrences all number	43	55
POLYNEUROPATHY
subjects affected / exposed	13 / 225 (5.78%)	13 / 226 (5.75%)
occurrences all number	15	17
DYSGEUSIA
subjects affected / exposed	35 / 225 (15.56%)	32 / 226 (14.16%)
occurrences all number	40	36
HEADACHE
subjects affected / exposed	48 / 225 (21.33%)	52 / 226 (23.01%)
occurrences all number	67	81
PARAESTHESIA
subjects affected / exposed	20 / 225 (8.89%)	15 / 226 (6.64%)
occurrences all number	24	16
DIZZINESS
subjects affected / exposed	22 / 225 (9.78%)	23 / 226 (10.18%)
occurrences all number	29	29
HYPOAESTHESIA
subjects affected / exposed	9 / 225 (4.00%)	14 / 226 (6.19%)
occurrences all number	11	15
NEUROPATHY PERIPHERAL
subjects affected / exposed	43 / 225 (19.11%)	43 / 226 (19.03%)
occurrences all number	58	49
Blood and lymphatic system disorders
LYMPHOPENIA
subjects affected / exposed	13 / 225 (5.78%)	11 / 226 (4.87%)
occurrences all number	28	21
NEUTROPENIA
subjects affected / exposed	76 / 225 (33.78%)	66 / 226 (29.20%)
occurrences all number	188	168
ANAEMIA
subjects affected / exposed	114 / 225 (50.67%)	114 / 226 (50.44%)
occurrences all number	217	173
THROMBOCYTOPENIA
subjects affected / exposed	20 / 225 (8.89%)	22 / 226 (9.73%)
occurrences all number	40	31
LEUKOPENIA
subjects affected / exposed	50 / 225 (22.22%)	37 / 226 (16.37%)
occurrences all number	122	105
Eye disorders
DRY EYE
subjects affected / exposed	8 / 225 (3.56%)	15 / 226 (6.64%)
occurrences all number	8	15
Gastrointestinal disorders
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	14 / 225 (6.22%)	12 / 226 (5.31%)
occurrences all number	16	19
CONSTIPATION
subjects affected / exposed	59 / 225 (26.22%)	67 / 226 (29.65%)
occurrences all number	78	92
VOMITING
subjects affected / exposed	53 / 225 (23.56%)	77 / 226 (34.07%)
occurrences all number	86	116
DRY MOUTH
subjects affected / exposed	14 / 225 (6.22%)	13 / 226 (5.75%)
occurrences all number	15	13
DIARRHOEA
subjects affected / exposed	137 / 225 (60.89%)	145 / 226 (64.16%)
occurrences all number	271	333
NAUSEA
subjects affected / exposed	138 / 225 (61.33%)	145 / 226 (64.16%)
occurrences all number	281	313
STOMATITIS
subjects affected / exposed	44 / 225 (19.56%)	49 / 226 (21.68%)
occurrences all number	54	66
ABDOMINAL PAIN
subjects affected / exposed	21 / 225 (9.33%)	15 / 226 (6.64%)
occurrences all number	23	16
DYSPEPSIA
subjects affected / exposed	27 / 225 (12.00%)	25 / 226 (11.06%)
occurrences all number	41	27
ABDOMINAL PAIN UPPER
subjects affected / exposed	29 / 225 (12.89%)	25 / 226 (11.06%)
occurrences all number	36	29
HAEMORRHOIDS
subjects affected / exposed	14 / 225 (6.22%)	16 / 226 (7.08%)
occurrences all number	15	16
Skin and subcutaneous tissue disorders
RASH
subjects affected / exposed	46 / 225 (20.44%)	65 / 226 (28.76%)
occurrences all number	58	96
ONYCHOLYSIS
subjects affected / exposed	6 / 225 (2.67%)	13 / 226 (5.75%)
occurrences all number	9	15
DERMATITIS
subjects affected / exposed	13 / 225 (5.78%)	20 / 226 (8.85%)
occurrences all number	14	22
PRURITUS
subjects affected / exposed	23 / 225 (10.22%)	33 / 226 (14.60%)
occurrences all number	33	38
ERYTHEMA
subjects affected / exposed	17 / 225 (7.56%)	12 / 226 (5.31%)
occurrences all number	23	19
NAIL DISORDER
subjects affected / exposed	21 / 225 (9.33%)	17 / 226 (7.52%)
occurrences all number	21	19
ALOPECIA
subjects affected / exposed	141 / 225 (62.67%)	145 / 226 (64.16%)
occurrences all number	150	149
DRY SKIN
subjects affected / exposed	20 / 225 (8.89%)	21 / 226 (9.29%)
occurrences all number	21	23
NAIL DISCOLOURATION
subjects affected / exposed	24 / 225 (10.67%)	17 / 226 (7.52%)
occurrences all number	24	17
Renal and urinary disorders
DYSURIA
subjects affected / exposed	16 / 225 (7.11%)	19 / 226 (8.41%)
occurrences all number	20	23
Endocrine disorders
HYPERTHYROIDISM
subjects affected / exposed	6 / 225 (2.67%)	22 / 226 (9.73%)
occurrences all number	7	25
HYPOTHYROIDISM
subjects affected / exposed	21 / 225 (9.33%)	48 / 226 (21.24%)
occurrences all number	23	59
Musculoskeletal and connective tissue disorders
BACK PAIN
subjects affected / exposed	18 / 225 (8.00%)	22 / 226 (9.73%)
occurrences all number	20	27
BONE PAIN
subjects affected / exposed	16 / 225 (7.11%)	14 / 226 (6.19%)
occurrences all number	19	15
ARTHRALGIA
subjects affected / exposed	51 / 225 (22.67%)	51 / 226 (22.57%)
occurrences all number	78	75
MYALGIA
subjects affected / exposed	41 / 225 (18.22%)	45 / 226 (19.91%)
occurrences all number	65	61
PAIN IN EXTREMITY
subjects affected / exposed	23 / 225 (10.22%)	25 / 226 (11.06%)
occurrences all number	31	38
Infections and infestations
NASOPHARYNGITIS
subjects affected / exposed	15 / 225 (6.67%)	17 / 226 (7.52%)
occurrences all number	17	20
CONJUNCTIVITIS
subjects affected / exposed	17 / 225 (7.56%)	14 / 226 (6.19%)
occurrences all number	17	16
PARONYCHIA
subjects affected / exposed	13 / 225 (5.78%)	13 / 226 (5.75%)
occurrences all number	16	13
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	19 / 225 (8.44%)	19 / 226 (8.41%)
occurrences all number	20	23
URINARY TRACT INFECTION
subjects affected / exposed	24 / 225 (10.67%)	23 / 226 (10.18%)
occurrences all number	29	33
Metabolism and nutrition disorders
HYPERGLYCAEMIA
subjects affected / exposed	4 / 225 (1.78%)	13 / 226 (5.75%)
occurrences all number	5	15
HYPOKALAEMIA
subjects affected / exposed	10 / 225 (4.44%)	12 / 226 (5.31%)
occurrences all number	12	15
HYPOMAGNESAEMIA
subjects affected / exposed	14 / 225 (6.22%)	12 / 226 (5.31%)
occurrences all number	22	20
DECREASED APPETITE
subjects affected / exposed	34 / 225 (15.11%)	45 / 226 (19.91%)
occurrences all number	43	61

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Were there any global substantial amendments to the protocol? Yes

22 Mar 2019

The following updates were made: [1] Trastuzumab emtansine was added as a therapeutic optional therapy in combination with atezolizumab/placebo in the adjuvant setting for participants who did not achieve pathological complete response (pCR); [2] Secondary efficacy endpoints were added; [3] Tissue requirements at screening were clarified; [4] Participants with synchronous bilateral invasive breast cancer, ulcerating and inflammatory breast cancer were excluded; [5] Trastuzumab emtansine, doxorubicin, cyclophosphamide, and paclitaxel were included as investigational medicinal products; [6] Screening mammograms were performed prior to the start of the study; [7] Updated information regarding immune-related nephritis and immune-related myositis risks associated with the administration of atezolizumab; [8] Reference to the continuation and discontinuation of study treatment on the basis of left ventricular ejection fraction (LVEF) measurements.

04 Jun 2019

The following updates were made: [1] To provide statistical power to test the primary endpoint of pathological complete response (pCR); [2] An extended China enrollment was added; [3] Participant population and the study rationale was updated; [4] Clarifications were added in regards to the full axillary lymph node dissection; [5] The approved dosage and administration for atezolizumab was added; [6] Clarification of the requirements for performing breast imaging and the performance and intent of tumor assessments; [7] The prescribing information was specified; [8] There was an increase in sites and sample size; [9] Revisions were made to align with the Atezolizumab Investigator's Brochure.

14 Feb 2020

The following updates were made: [1] Protocol aligns with atezolizumab Investigator’s Brochure, Version 15; [2] Updates to management guidelines for infusion-related reactions; [3] “Immune-related” was changed to “immune-mediated;” [4] The atezolizumab AE management guidelines for immune mediated myocarditis was revised; [5] The list of potential risks for atezolizumab was revised; [6] Exclusion criteria was updated; [7] Investigational therapy was no longer prohibited during the duration of the study; [8] Clarification that data on breast cancer surgery and pathological assessment was collected from participants who discontinued study treatment during the neoadjuvant phase; [9] Certain participants in the adjuvant phase were not required to provide PK and ADA samples; [10] Participants who discontinued treatment with trastuzumab emtansine for pneumonitis had to discontinue all study treatment.

12 Feb 2021

The following updates were made: [1] The independent Data Monitoring Committee (iDMC) recommended to stop treatment with atezolizumab/placebo; [2] China extension phase was cancelled; [3] PK and ADA samples for atezolizumab, trastuzumab and pertuzumab was discontinued during the study treatment phase; [4] Participants would enter the follow-up phase and undergo follow up assessments regardless of reason for discontinuing; [5] Extension of the LVEF assessments; [6] Clarification of continuation of HER2-targeted therapy following Medical Monitor approval; [7] Updates to appendices 9 and 12; [8] Alignment with Investigator's Brochure v17.

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.

On February 5, 2021, the experimental treatment was discontinued and unblinded following the recommendation of the independent Data Monitoring Committee (iDMC) to stop treatment with atezolizumab/placebo.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants with Pathological Complete Response (pCR) in the PD-L1-Positive Population (IC 1/2/3)

Primary: Percentage of Participants with Pathological Complete Response (pCR) in the PD-L1-Positive Population (IC 1/2/3)

Primary: pCR in the ITT Population

Primary: pCR in the ITT Population

Secondary: Percentage of Participants with pCR Based on Hormone Receptor Status

Secondary: Percentage of Participants with pCR Based on Hormone Receptor Status

Secondary: Percentage of Participants with pCR in the PD-L1-Negative Population

Secondary: Percentage of Participants with pCR in the PD-L1-Negative Population

Secondary: Event-Free Survival (EFS)

Secondary: Event-Free Survival (EFS)

Secondary: Disease-Free Survival (DFS)

Secondary: Disease-Free Survival (DFS)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Mean Changes From Baseline in Function (Role, Physical)

Secondary: Mean Changes From Baseline in Function (Role, Physical)

Secondary: Mean Changes From Baseline in Global Health Status

Secondary: Mean Changes From Baseline in Global Health Status

Secondary: Percentage of Participants With Adverse Events

Secondary: Percentage of Participants With Adverse Events

Secondary: Maximum Serum Concentration (Cmax) of Atezolizumab

Secondary: Maximum Serum Concentration (Cmax) of Atezolizumab

Secondary: Minimum Serum Concentration (Cmin) of Atezolizumab

Secondary: Minimum Serum Concentration (Cmin) of Atezolizumab

Secondary: Trough Concentration (Ctrough) for Pertuzumab and Trastuzumab in Serum

Secondary: Trough Concentration (Ctrough) for Pertuzumab and Trastuzumab in Serum

Secondary: Cmin of Trastuzumab Emtansine in Serum

Secondary: Cmin of Trastuzumab Emtansine in Serum

Secondary: Cmax of Trastuzumab Emtansine in Serum

Secondary: Cmax of Trastuzumab Emtansine in Serum

Secondary: Number of Participants with Treatment-Emergent Anti-Drug Antibodies (ADAs) to Atezolizumab

Secondary: Number of Participants with Treatment-Emergent Anti-Drug Antibodies (ADAs) to Atezolizumab

Secondary: Number of Participants with Treatment-Emergent ADAs to Trastuzumab

Secondary: Number of Participants with Treatment-Emergent ADAs to Trastuzumab

Secondary: Number of Participants with Treatment-Emergent ADAs to Pertuzumab

Secondary: Number of Participants with Treatment-Emergent ADAs to Pertuzumab

Secondary: Percentage of Particpants with pCR Based on PIK3CA Mutation Status

Secondary: Percentage of Particpants with pCR Based on PIK3CA Mutation Status

Secondary: Number of Participants with Treatment-Emergent ADAs to Trastuzumab Emtansine

Secondary: Number of Participants with Treatment-Emergent ADAs to Trastuzumab Emtansine

Secondary: EFS Based on PIK3CA Mutation Status

Secondary: EFS Based on PIK3CA Mutation Status

Secondary: DFS Based on PIK3CA Mutation Status

Secondary: DFS Based on PIK3CA Mutation Status

Secondary: OS Based on PIK3CA Mutation Status

Secondary: OS Based on PIK3CA Mutation Status

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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