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Clinical Trial Results:
A Randomized, Multicenter, Double-blind, Placebo-controlled Phase 3 Study of Nivolumab Versus Placebo in Combination With Neoadjuvant Chemotherapy and Adjuvant Endocrine Therapy in Patients With High-risk, Estrogen Receptor-Positive (ER+), Human Epidermal Growth Factor Receptor 2-Negative (HER2-) Primary Breast Cancer (CheckMate 7FL: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 7FL)

Summary
EudraCT number	2019-002469-37
Trial protocol	AT DE CZ FR PL NL BE DK FI IE ES PT GB IT RO
Global end of trial date	27 Dec 2023

Results information
Results version number	v1(current)
This version publication date	01 Jan 2025
First version publication date	01 Jan 2025
Other versions

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

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Trial information

Top of page

Sponsor protocol code

CA209-7FL

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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 Mar 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

27 Dec 2023

Was the trial ended prematurely?

Main objective of the trial

Assess the efficacy and safety of nivolumab or nivolumab placebo combined with standard neoadjuvant anthracycline-taxane-based chemotherapy, followed by nivolumab combined with endocrine therapy (ET) or ET alone as adjuvant treatment, in participants with high-risk, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer (BC).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Nov 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 36

Country: Number of subjects enrolled

Argentina: 46

Country: Number of subjects enrolled

Australia: 25

Country: Number of subjects enrolled

Austria: 17

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Brazil: 42

Country: Number of subjects enrolled

Canada: 6

Country: Number of subjects enrolled

Chile: 29

Country: Number of subjects enrolled

China: 28

Country: Number of subjects enrolled

Colombia: 35

Country: Number of subjects enrolled

Czechia: 1

Country: Number of subjects enrolled

Denmark: 5

Country: Number of subjects enrolled

Finland: 5

Country: Number of subjects enrolled

France: 19

Country: Number of subjects enrolled

Germany: 25

Country: Number of subjects enrolled

Ireland: 3

Country: Number of subjects enrolled

Italy: 28

Country: Number of subjects enrolled

Mexico: 65

Country: Number of subjects enrolled

Netherlands: 4

Country: Number of subjects enrolled

Poland: 13

Country: Number of subjects enrolled

Portugal: 2

Country: Number of subjects enrolled

Romania: 25

Country: Number of subjects enrolled

Russian Federation: 23

Country: Number of subjects enrolled

Singapore: 6

Country: Number of subjects enrolled

Spain: 18

Country: Number of subjects enrolled

Switzerland: 1

Country: Number of subjects enrolled

Türkiye: 12

Country: Number of subjects enrolled

United Kingdom: 1

Worldwide total number of subjects

521

EEA total number of subjects

166

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)

450

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

2 Participants planned for Arm B treatment received Arm A treatment.

Period 1 title

Pre-treatment

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Arm A

Arm description

Neoadjuvant (Pre-surgery) Phase 8 cycles maximum: Paclitaxel (PTX) Cycles 1-4 (1 cycle = Q3W): Nivolumab 360 mg Q3W + PTX QW Followed by: Anthracycline-Cyclophosphamide (AC) Cycles 1-4 (1 cycle = Q2W or Q3W): Nivolumab 360 mg Q3W + AC Q3W or Nivolumab 240 mg Q2W + AC Q2W Surgery and Adjuvant (Post-surgery) Phase 7 cycles maximum: Adjuvant Cycles 1-7 (1 cycle = Q4W): Nivolumab 480 mg Q4W + Endocrine Therapy (ET)

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

PTX

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

80 mg/m^2 weekly

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

360 mg Q3W

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

240 mg Q2W

Investigational medicinal product name

Endocrine Therapy

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

May include tamoxifen, letrozole, anastrozole, or exemestane, to be administered per the respective package inserts

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

60 mg/m^2 Q2W or Q3W determined by the Investigator

Investigational medicinal product name

Epirubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

90 mg/m^2 Q2W or Q3W determined by the Investigator

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

600 mg/m^2 Q2W or Q3W determined by the Investigator

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

480 mg Q4W

Arm B

Arm description

Neoadjuvant (Pre-surgery) Phase 8 cycles maximum: Paclitaxel (PTX) Cycles 1-4 (1 cycle = Q3W): Nivolumab Placebo Q3W + PTX QW Followed by: Anthracycline-Cyclophosphamide (AC) Cycles 1-4 (1 cycle = Q2W or Q3W): Nivolumab Placebo Q3W + AC Q3W or Nivolumab Placebo Q2W + AC Q2W Surgery and Adjuvant (Post-surgery) Phase 7 cycles maximum: Adjuvant Cycles 1-7 (1 cycle = Q4W): Endocrine Therapy (ET)

Arm type

Active comparator

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

PTX

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

80 mg/m^2 weekly

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Q3W

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Q2W

Investigational medicinal product name

Endocrine Therapy

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

May include tamoxifen, letrozole, anastrozole, or exemestane, to be administered per the respective package inserts

Investigational medicinal product name

Epirubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

90 mg/m^2 Q2W or Q3W determined by the Investigator

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

600 mg/m^2 Q2W or Q3W determined by the Investigator

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

60 mg/m^2 Q2W or Q3W determined by the Investigator

Number of subjects in period 1	Arm A	Arm B
Started	263	258
Completed	260	257
Not completed	3	1
Participant withdrew consent	2	-
Participant no longer meets study criteria	1	1

Period 2 title

Treatment

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Arm A

Arm description

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

PTX

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

80 mg/m^2 weekly

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

60 mg/m^2 Q2W or Q3W determined by the Investigator

Investigational medicinal product name

Epirubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

90 mg/m^2 Q2W or Q3W determined by the Investigator

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

600 mg/m^2 Q2W or Q3W determined by the Investigator

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

480 mg Q4W

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

360 mg Q3W

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

240 mg Q2W

Investigational medicinal product name

Endocrine Therapy

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

May include tamoxifen, letrozole, anastrozole, or exemestane, to be administered per the respective package inserts

Arm B

Arm description

Arm type

Active comparator

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

PTX

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

80 mg/m^2 weekly

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

60 mg/m^2 Q2W or Q3W determined by the Investigator

Investigational medicinal product name

Epirubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

90 mg/m^2 Q2W or Q3W determined by the Investigator

Investigational medicinal product name

Endocrine Therapy

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

May include tamoxifen, letrozole, anastrozole, or exemestane, to be administered per the respective package inserts

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Q3W

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Q2W

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

600 mg/m^2 Q2W or Q3W determined by the Investigator

Number of subjects in period 2	Arm A	Arm B
Started	260	257
Received Arm A Treatment	0 ^[1]	2 ^[2]
Completed	167	174
Not completed	93	83
Adverse event, serious fatal	3	-
Adverse Event unrelated to Study drug	1	-
Participant no longer meets study criteria	2	2
Other reasons	17	23
Administrative reasons by sponsor	2	3
Disease Progression	4	7
Consent withdrawn by subject	8	8
Adverse event, non-fatal	23	7
Participant request to discontinue Study treatment	15	14
Study drug toxicity	12	5
Not reported	4	8
Disease Recurrence	-	2
Lack of efficacy	2	4

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Represents the subjects that received arm A treatment
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Represents the subjects that received arm A treatment

Baseline characteristics

Top of page

Reporting group title

Arm A

Reporting group description

Reporting group title

Arm B

Reporting group description

Reporting group values	Arm A	Arm B	Total
Number of subjects	263	258	521
Age categorical
Units:
Age Continuous
Units: years
arithmetic mean (standard deviation)	49.9 ( 12.0 )	50.9 ( 11.8 )	-
Sex: Female, Male
Units: Participants
Female	262	257	519
Male	1	1	2
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	18	17	35
Asian	24	18	42
Native Hawaiian or Other Pacific Islander	2	3	5
Black or African American	6	8	14
White	202	193	395
More than one race	0	0	0
Unknown or Not Reported	11	19	30
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	74	80	154
Not Hispanic or Latino	102	121	223
Unknown or Not Reported	87	57	144

End points

Top of page

Reporting group title

Arm A

Reporting group description

Reporting group title

Arm B

Reporting group description

Reporting group title

Arm A

Reporting group description

Reporting group title

Arm B

Reporting group description

Primary: Pathological Complete Response (pCR) Rate

Top of page

End point title

Pathological Complete Response (pCR) Rate

End point description

pCR rate is defined as the percentage of participants who achieved pCR. pCR is defined as no invasive residual disease in breast and lymph nodes performed by a local pathologist. Criteria for evaluation of pCR includes the following: pCR in breast, axillary lymph nodes and non-axillary sentinel node; no histologic evidence of invasive tumor cells; and pCR in the breast.

End point type

Primary

End point timeframe

Up to approximately 37 months

End point values	Arm A	Arm B
Number of subjects analysed	257	253
Units: Percentage of participants
number (confidence interval 95%)	24.5 (19.4 to 30.2)	13.8 (9.8 to 18.7)

Adjusted Difference of pCR Rates

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

510

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Adjusted Difference of pCR Rates

Point estimate

10.5

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

16.9

Odds Ratio (OR)

Statistical analysis description

Arm A over Arm B

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

510

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0021

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

2.05

Confidence interval

level

95%

sides

2-sided

lower limit

1.29

upper limit

3.27

Secondary: Pathological Complete Response (pCR) Rate (PD-L1 >=1%)

Top of page

End point title

Pathological Complete Response (pCR) Rate (PD-L1 >=1%)

End point description

End point type

Secondary

End point timeframe

Up to approximately 37 months

End point values	Arm A	Arm B
Number of subjects analysed	88	84
Units: Percentage of participants
number (confidence interval 95%)	44.3 (33.7 to 55.3)	20.2 (12.3 to 30.4)

Odds Ratio (OR)

Statistical analysis description

Arm A over Arm B

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Odds ratio (OR)

Point estimate

3.11

Confidence interval

level

95%

sides

2-sided

lower limit

1.58

upper limit

6.11

Adjusted Difference of pCR Rates

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Adjusted Difference of pCR Rates

Point estimate

24.1

Confidence interval

level

95%

sides

2-sided

lower limit

10.7

upper limit

37.5

Secondary: Number of Participants with Residual Cancer Burden (RCB)

Top of page

End point title

Number of Participants with Residual Cancer Burden (RCB)

End point description

RCB is estimated from routine pathologic sections of the primary breast tumor site and the regional lymph nodes after the completion of neoadjuvant therapy. RCB is categorized into the following 4 classes: RCB-0: no residual disease; RCB-1: minimal residual disease; RCB-II: moderate residual disease; RCB-III: and extensive residual disease.

End point type

Secondary

End point timeframe

Up to approximately 37 months

End point values	Arm A	Arm B
Number of subjects analysed	257	253
Units: Participants
RCB-0	62	34
RCB-I	17	20
RCB-II	90	106
RCB-III	57	73
Not Reported	31	20

No statistical analyses for this end point

Secondary: Number of Participants with Residual Cancer Burden (RCB) PD-L1 >=1%

Top of page

End point title

Number of Participants with Residual Cancer Burden (RCB) PD-L1 >=1%

End point description

End point type

Secondary

End point timeframe

Up to approximately 37 months

End point values	Arm A	Arm B
Number of subjects analysed	88	84
Units: Participants
RCB-0	38	16
RCB-I	10	6
RCB-II	25	36
RCB-III	9	20
Not Reported	6	6

No statistical analyses for this end point

Secondary: Number of Participants with Adverse Events (AEs)

Top of page

End point title

Number of Participants with Adverse Events (AEs)

End point description

Number of participants with any grade adverse events (AEs). An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment that does not necessarily have a causal relation with this treatment. Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

End point type

Secondary

End point timeframe

From first dose to 30 days post last dose of neoadjuvant or adjuvant study therapy (Up to approximately 19 months)

End point values	Arm A	Arm B
Number of subjects analysed	262	255
Units: participants
Adverse Events (AEs)	259	252
Drug-Related AEs	254	236
AEs leading to discontinuation	41	14

No statistical analyses for this end point

Secondary: Number of Participants with Serious Adverse Events (SAEs)

Top of page

End point title

Number of Participants with Serious Adverse Events (SAEs)

End point description

Number of participants with any grade serious adverse events (SAE). SAE is defined as any untoward medical occurrence that, at any dose: Results in death; is life threatening; requires inpatient hospitalization; results in persistent or significant disability; is a congenital anomaly/birth defect. Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

End point type

Secondary

End point timeframe

From first dose to 30 days post last dose of neoadjuvant or adjuvant study therapy (Up to approximately 19 months)

End point values	Arm A	Arm B
Number of subjects analysed	262	255
Units: participants	80	45

No statistical analyses for this end point

Secondary: Number of Participants Who Died

Top of page

End point title

Number of Participants Who Died

End point description

Number of participants who died due to any cause.

End point type

Secondary

End point timeframe

Up to approximately 41 months

End point values	Arm A	Arm B
Number of subjects analysed	262	255
Units: participants	15	8

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Participants were assessed for all-cause mortality from their first dose to their study completion (up to approximately 41 months). SAEs and Other AEs were assessed from first dose up to 100 days post last dose (Up to approximately 21 months).

Adverse event reporting additional description

The number at Risk for All-Cause Mortality represents all Randomized Participants based on the treatment received. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Arm A: Nivo + Chemo (PTX QW + AC Q3W) / Nivo + ET

Reporting group description

Neoadjuvant (Pre-surgery) Phase 8 cycles maximum: Paclitaxel (PTX) Cycles 1-4 (1 cycle = Q3W): Nivolumab 360 mg Q3W + PTX QW Followed by: Anthracycline-Cyclophosphamide (AC) Cycles 1-4 (1 cycle = Q3W): Nivolumab 360 mg Q3W + AC Q3W Surgery and Adjuvant (Post-surgery) Phase 7 cycles maximum: Adjuvant Cycles 1-7 (1 cycle = Q4W): Nivolumab 480 mg Q4W + Endocrine Therapy (ET)

Reporting group title

Arm B: Nivo Placebo + Chemo (PTX QW + AC Q2W) / ET

Reporting group description

Neoadjuvant (Pre-surgery) Phase 8 cycles maximum: Paclitaxel (PTX) Cycles 1-4 (1 cycle = Q3W): Nivolumab Placebo Q3W + PTX QW Followed by: Anthracycline-Cyclophosphamide (AC) Cycles 1-4 (1 cycle = Q2W): Nivolumab Placebo Q2W + AC Q2W Surgery and Adjuvant (Post-surgery) Phase 7 cycles maximum: Adjuvant Cycles 1-7 (1 cycle = Q4W): Endocrine Therapy (ET)

Reporting group title

Arm B: Nivo Placebo + Chemo (PTX QW + AC Q3W) / ET

Reporting group description

Neoadjuvant (Pre-surgery) Phase 8 cycles maximum: Paclitaxel (PTX) Cycles 1-4 (1 cycle = Q3W): Nivolumab Placebo Q3W + PTX QW Followed by: Anthracycline-Cyclophosphamide (AC) Cycles 1-4 (1 cycle = Q3W): Nivolumab Placebo Q3W + AC Q3W Surgery and Adjuvant (Post-surgery) Phase 7 cycles maximum: Adjuvant Cycles 1-7 (1 cycle = Q4W): Endocrine Therapy (ET)

Reporting group title

Arm A: Nivo + Chemo (PTX QW + AC Q2W) / Nivo + ET

Reporting group description

Neoadjuvant (Pre-surgery) Phase 8 cycles maximum: Paclitaxel (PTX) Cycles 1-4 (1 cycle = Q3W): Nivolumab 360 mg Q3W + PTX QW Followed by: Anthracycline-Cyclophosphamide (AC) Cycles 1-4 (1 cycle = Q2W): Nivolumab 240 mg Q2W + AC Q2W Surgery and Adjuvant (Post-surgery) Phase 7 cycles maximum: Adjuvant Cycles 1-7 (1 cycle = Q4W): Nivolumab 480 mg Q4W + Endocrine Therapy (ET)

Serious adverse events	Arm A: Nivo + Chemo (PTX QW + AC Q3W) / Nivo + ET	Arm B: Nivo Placebo + Chemo (PTX QW + AC Q2W) / ET	Arm B: Nivo Placebo + Chemo (PTX QW + AC Q3W) / ET	Arm A: Nivo + Chemo (PTX QW + AC Q2W) / Nivo + ET
Total subjects affected by serious adverse events
subjects affected / exposed	38 / 127 (29.92%)	26 / 132 (19.70%)	20 / 123 (16.26%)	51 / 135 (37.78%)
number of deaths (all causes)	8	4	4	7
number of deaths resulting from adverse events	6	1	0	5
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to central nervous system
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	1 / 123 (0.81%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	2 / 127 (1.57%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Cervix carcinoma
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Arterial thrombosis
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Deep vein thrombosis
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	1 / 123 (0.81%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 127 (0.79%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	1 / 123 (0.81%)	0 / 135 (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
General disorders and administration site conditions
Death
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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 / 1
Disease progression
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Pyrexia
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	4 / 135 (2.96%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Malaise
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Immune system disorders
Anaphylactic shock
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Anaphylactic reaction
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Reproductive system and breast disorders
Breast inflammation
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Immune-mediated lung disease
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Pulmonary embolism
subjects affected / exposed	2 / 127 (1.57%)	0 / 132 (0.00%)	0 / 123 (0.00%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Interstitial lung disease
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Product issues
Device occlusion
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Investigations
White blood cell count decreased
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Neutrophil count decreased
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inflammatory marker increased
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Blood creatinine increased
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Liver function test increased
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Injury, poisoning and procedural complications
Radiation skin injury
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Craniofacial fracture
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Ankle fracture
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	1 / 123 (0.81%)	0 / 135 (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
Post procedural haematoma
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	1 / 123 (0.81%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical procedure repeated
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Cardiac disorders
Cardio-respiratory arrest
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Myocardial infarction
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	1 / 123 (0.81%)	0 / 135 (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
Pericardial effusion
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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 / 1
Supraventricular tachycardia
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Cardiac failure
subjects affected / exposed	1 / 127 (0.79%)	1 / 132 (0.76%)	0 / 123 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac perfusion defect
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Cardiac failure congestive
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	1 / 123 (0.81%)	0 / 135 (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
Nervous system disorders
Syncope
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Intracranial pressure increased
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Headache
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Guillain-Barre syndrome
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Epilepsy
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	1 / 123 (0.81%)	0 / 135 (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
Cerebellar syndrome
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Myelosuppression
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Anaemia
subjects affected / exposed	2 / 127 (1.57%)	0 / 132 (0.00%)	0 / 123 (0.00%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	3 / 127 (2.36%)	4 / 132 (3.03%)	0 / 123 (0.00%)	9 / 135 (6.67%)
occurrences causally related to treatment / all	3 / 3	4 / 4	0 / 0	10 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	2 / 127 (1.57%)	0 / 132 (0.00%)	2 / 123 (1.63%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 2	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	1 / 123 (0.81%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Gastrointestinal disorders
Gastritis
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Diarrhoea
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	2 / 123 (1.63%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	1 / 123 (0.81%)	0 / 135 (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
Abdominal pain upper
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Abdominal pain
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Nausea
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 127 (0.79%)	1 / 132 (0.76%)	1 / 123 (0.81%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Hepatobiliary disorders
Hepatitis cholestatic
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Hepatitis
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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	1 / 1
Cholelithiasis
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Cholecystitis
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Autoimmune hepatitis
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Skin and subcutaneous tissue disorders
Rash macular
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Urticaria
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Pemphigoid
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Rash
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Pruritus
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Renal and urinary disorders
Urinary retention
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Glomerulonephritis
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Acute kidney injury
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	1 / 123 (0.81%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Thyroiditis subacute
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Immune-mediated adrenal insufficiency
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Hypopituitarism
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Adrenal insufficiency
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
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 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Myositis
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Infections and infestations
Breast abscess
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	1 / 123 (0.81%)	0 / 135 (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
Infection
subjects affected / exposed	1 / 127 (0.79%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mastitis
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	1 / 123 (0.81%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Device related infection
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	1 / 123 (0.81%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic infection
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	1 / 123 (0.81%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	1 / 123 (0.81%)	0 / 135 (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
Catheter site infection
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
COVID-19 pneumonia
subjects affected / exposed	3 / 127 (2.36%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	2 / 127 (1.57%)	1 / 132 (0.76%)	2 / 123 (1.63%)	5 / 135 (3.70%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Breast cellulitis
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	1 / 123 (0.81%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
SARS-CoV-2 sepsis
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Sepsis
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Neutropenic sepsis
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Perirectal abscess
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Pneumocystis jirovecii infection
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Pneumonia
subjects affected / exposed	1 / 127 (0.79%)	3 / 132 (2.27%)	1 / 123 (0.81%)	3 / 135 (2.22%)
occurrences causally related to treatment / all	0 / 1	4 / 4	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Postoperative wound infection
subjects affected / exposed	2 / 127 (1.57%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Skin infection
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	1 / 123 (0.81%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Vascular access site infection
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Urinary tract infection
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	1 / 123 (0.81%)	0 / 135 (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
Upper respiratory tract infection
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Systemic infection
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Metabolism and nutrition disorders
Diabetic ketoacidosis
subjects affected / exposed	1 / 127 (0.79%)	0 / 132 (0.00%)	0 / 123 (0.00%)	0 / 135 (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
Dehydration
subjects affected / exposed	0 / 127 (0.00%)	1 / 132 (0.76%)	0 / 123 (0.00%)	0 / 135 (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
Hyponatraemia
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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
Hypophagia
subjects affected / exposed	0 / 127 (0.00%)	0 / 132 (0.00%)	0 / 123 (0.00%)	1 / 135 (0.74%)
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

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

Non-serious adverse events	Arm A: Nivo + Chemo (PTX QW + AC Q3W) / Nivo + ET	Arm B: Nivo Placebo + Chemo (PTX QW + AC Q2W) / ET	Arm B: Nivo Placebo + Chemo (PTX QW + AC Q3W) / ET	Arm A: Nivo + Chemo (PTX QW + AC Q2W) / Nivo + ET
Total subjects affected by non serious adverse events
subjects affected / exposed	126 / 127 (99.21%)	130 / 132 (98.48%)	120 / 123 (97.56%)	132 / 135 (97.78%)
Vascular disorders
Hypertension
subjects affected / exposed	11 / 127 (8.66%)	7 / 132 (5.30%)	5 / 123 (4.07%)	9 / 135 (6.67%)
occurrences all number	12	10	5	12
Hot flush
subjects affected / exposed	9 / 127 (7.09%)	30 / 132 (22.73%)	12 / 123 (9.76%)	33 / 135 (24.44%)
occurrences all number	12	34	12	35
Lymphoedema
subjects affected / exposed	2 / 127 (1.57%)	7 / 132 (5.30%)	2 / 123 (1.63%)	5 / 135 (3.70%)
occurrences all number	2	8	2	5
Flushing
subjects affected / exposed	0 / 127 (0.00%)	7 / 132 (5.30%)	3 / 123 (2.44%)	7 / 135 (5.19%)
occurrences all number	0	10	4	7
General disorders and administration site conditions
Illness
subjects affected / exposed	7 / 127 (5.51%)	1 / 132 (0.76%)	2 / 123 (1.63%)	0 / 135 (0.00%)
occurrences all number	13	1	5	0
Fatigue
subjects affected / exposed	34 / 127 (26.77%)	52 / 132 (39.39%)	24 / 123 (19.51%)	67 / 135 (49.63%)
occurrences all number	47	86	32	104
Chills
subjects affected / exposed	1 / 127 (0.79%)	2 / 132 (1.52%)	1 / 123 (0.81%)	8 / 135 (5.93%)
occurrences all number	1	2	1	9
Asthenia
subjects affected / exposed	27 / 127 (21.26%)	27 / 132 (20.45%)	30 / 123 (24.39%)	25 / 135 (18.52%)
occurrences all number	72	37	143	27
Mucosal inflammation
subjects affected / exposed	7 / 127 (5.51%)	19 / 132 (14.39%)	6 / 123 (4.88%)	16 / 135 (11.85%)
occurrences all number	7	20	8	19
Pain
subjects affected / exposed	5 / 127 (3.94%)	3 / 132 (2.27%)	2 / 123 (1.63%)	11 / 135 (8.15%)
occurrences all number	8	3	2	13
Pyrexia
subjects affected / exposed	11 / 127 (8.66%)	10 / 132 (7.58%)	7 / 123 (5.69%)	21 / 135 (15.56%)
occurrences all number	16	12	7	26
Oedema peripheral
subjects affected / exposed	5 / 127 (3.94%)	13 / 132 (9.85%)	6 / 123 (4.88%)	12 / 135 (8.89%)
occurrences all number	5	16	9	12
Immune system disorders
Hypersensitivity
subjects affected / exposed	8 / 127 (6.30%)	8 / 132 (6.06%)	5 / 123 (4.07%)	3 / 135 (2.22%)
occurrences all number	10	9	9	3
Reproductive system and breast disorders
Breast pain
subjects affected / exposed	4 / 127 (3.15%)	14 / 132 (10.61%)	6 / 123 (4.88%)	13 / 135 (9.63%)
occurrences all number	4	16	6	14
Respiratory, thoracic and mediastinal disorders
Rhinorrhoea
subjects affected / exposed	3 / 127 (2.36%)	0 / 132 (0.00%)	4 / 123 (3.25%)	7 / 135 (5.19%)
occurrences all number	4	0	5	7
Oropharyngeal pain
subjects affected / exposed	3 / 127 (2.36%)	6 / 132 (4.55%)	4 / 123 (3.25%)	7 / 135 (5.19%)
occurrences all number	3	8	7	7
Epistaxis
subjects affected / exposed	11 / 127 (8.66%)	12 / 132 (9.09%)	8 / 123 (6.50%)	9 / 135 (6.67%)
occurrences all number	14	12	8	10
Dyspnoea
subjects affected / exposed	4 / 127 (3.15%)	10 / 132 (7.58%)	9 / 123 (7.32%)	9 / 135 (6.67%)
occurrences all number	5	10	10	9
Cough
subjects affected / exposed	13 / 127 (10.24%)	16 / 132 (12.12%)	9 / 123 (7.32%)	29 / 135 (21.48%)
occurrences all number	14	17	11	34
Psychiatric disorders
Insomnia
subjects affected / exposed	8 / 127 (6.30%)	20 / 132 (15.15%)	8 / 123 (6.50%)	25 / 135 (18.52%)
occurrences all number	9	22	8	30
Depression
subjects affected / exposed	3 / 127 (2.36%)	8 / 132 (6.06%)	0 / 123 (0.00%)	7 / 135 (5.19%)
occurrences all number	3	8	0	7
Anxiety
subjects affected / exposed	6 / 127 (4.72%)	6 / 132 (4.55%)	2 / 123 (1.63%)	10 / 135 (7.41%)
occurrences all number	6	6	3	12
Investigations
Blood calcium increased
subjects affected / exposed	0 / 127 (0.00%)	3 / 132 (2.27%)	0 / 123 (0.00%)	7 / 135 (5.19%)
occurrences all number	0	4	0	7
Blood alkaline phosphatase increased
subjects affected / exposed	10 / 127 (7.87%)	5 / 132 (3.79%)	4 / 123 (3.25%)	9 / 135 (6.67%)
occurrences all number	13	5	9	10
Aspartate aminotransferase increased
subjects affected / exposed	32 / 127 (25.20%)	19 / 132 (14.39%)	23 / 123 (18.70%)	30 / 135 (22.22%)
occurrences all number	55	33	28	51
Alanine aminotransferase increased
subjects affected / exposed	27 / 127 (21.26%)	20 / 132 (15.15%)	23 / 123 (18.70%)	31 / 135 (22.96%)
occurrences all number	46	29	33	54
Blood glucose increased
subjects affected / exposed	0 / 127 (0.00%)	2 / 132 (1.52%)	0 / 123 (0.00%)	7 / 135 (5.19%)
occurrences all number	0	2	0	16
Blood lactate dehydrogenase increased
subjects affected / exposed	6 / 127 (4.72%)	9 / 132 (6.82%)	5 / 123 (4.07%)	6 / 135 (4.44%)
occurrences all number	7	10	9	7
Blood sodium decreased
subjects affected / exposed	0 / 127 (0.00%)	5 / 132 (3.79%)	0 / 123 (0.00%)	8 / 135 (5.93%)
occurrences all number	0	9	0	15
Blood thyroid stimulating hormone decreased
subjects affected / exposed	4 / 127 (3.15%)	3 / 132 (2.27%)	0 / 123 (0.00%)	11 / 135 (8.15%)
occurrences all number	4	3	0	11
Blood thyroid stimulating hormone increased
subjects affected / exposed	5 / 127 (3.94%)	4 / 132 (3.03%)	3 / 123 (2.44%)	15 / 135 (11.11%)
occurrences all number	6	9	4	23
Lymphocyte count decreased
subjects affected / exposed	4 / 127 (3.15%)	3 / 132 (2.27%)	2 / 123 (1.63%)	9 / 135 (6.67%)
occurrences all number	6	8	4	10
Neutrophil count decreased
subjects affected / exposed	20 / 127 (15.75%)	11 / 132 (8.33%)	11 / 123 (8.94%)	16 / 135 (11.85%)
occurrences all number	52	13	30	27
Weight decreased
subjects affected / exposed	7 / 127 (5.51%)	3 / 132 (2.27%)	3 / 123 (2.44%)	10 / 135 (7.41%)
occurrences all number	7	3	4	11
White blood cell count decreased
subjects affected / exposed	15 / 127 (11.81%)	5 / 132 (3.79%)	8 / 123 (6.50%)	9 / 135 (6.67%)
occurrences all number	49	8	26	17
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	12 / 127 (9.45%)	12 / 132 (9.09%)	10 / 123 (8.13%)	25 / 135 (18.52%)
occurrences all number	14	13	14	31
Procedural pain
subjects affected / exposed	3 / 127 (2.36%)	5 / 132 (3.79%)	5 / 123 (4.07%)	9 / 135 (6.67%)
occurrences all number	3	6	5	9
Radiation skin injury
subjects affected / exposed	15 / 127 (11.81%)	20 / 132 (15.15%)	13 / 123 (10.57%)	22 / 135 (16.30%)
occurrences all number	15	20	13	23
Cardiac disorders
Tachycardia
subjects affected / exposed	3 / 127 (2.36%)	4 / 132 (3.03%)	0 / 123 (0.00%)	8 / 135 (5.93%)
occurrences all number	4	4	0	8
Palpitations
subjects affected / exposed	2 / 127 (1.57%)	7 / 132 (5.30%)	1 / 123 (0.81%)	6 / 135 (4.44%)
occurrences all number	2	7	1	7
Nervous system disorders
Taste disorder
subjects affected / exposed	0 / 127 (0.00%)	9 / 132 (6.82%)	1 / 123 (0.81%)	3 / 135 (2.22%)
occurrences all number	0	10	1	4
Dizziness
subjects affected / exposed	9 / 127 (7.09%)	8 / 132 (6.06%)	7 / 123 (5.69%)	10 / 135 (7.41%)
occurrences all number	11	8	10	12
Dysgeusia
subjects affected / exposed	9 / 127 (7.09%)	14 / 132 (10.61%)	8 / 123 (6.50%)	26 / 135 (19.26%)
occurrences all number	10	14	8	26
Headache
subjects affected / exposed	24 / 127 (18.90%)	33 / 132 (25.00%)	24 / 123 (19.51%)	43 / 135 (31.85%)
occurrences all number	39	53	38	62
Neuropathy peripheral
subjects affected / exposed	26 / 127 (20.47%)	32 / 132 (24.24%)	19 / 123 (15.45%)	38 / 135 (28.15%)
occurrences all number	27	37	19	42
Paraesthesia
subjects affected / exposed	8 / 127 (6.30%)	13 / 132 (9.85%)	8 / 123 (6.50%)	10 / 135 (7.41%)
occurrences all number	10	17	8	11
Peripheral sensory neuropathy
subjects affected / exposed	8 / 127 (6.30%)	16 / 132 (12.12%)	10 / 123 (8.13%)	21 / 135 (15.56%)
occurrences all number	8	16	12	21
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	24 / 127 (18.90%)	24 / 132 (18.18%)	27 / 123 (21.95%)	26 / 135 (19.26%)
occurrences all number	39	36	57	45
Lymphopenia
subjects affected / exposed	15 / 127 (11.81%)	12 / 132 (9.09%)	8 / 123 (6.50%)	9 / 135 (6.67%)
occurrences all number	18	19	13	15
Leukopenia
subjects affected / exposed	8 / 127 (6.30%)	11 / 132 (8.33%)	12 / 123 (9.76%)	8 / 135 (5.93%)
occurrences all number	10	22	18	17
Anaemia
subjects affected / exposed	47 / 127 (37.01%)	62 / 132 (46.97%)	32 / 123 (26.02%)	65 / 135 (48.15%)
occurrences all number	76	86	58	99
Thrombocytopenia
subjects affected / exposed	2 / 127 (1.57%)	3 / 132 (2.27%)	1 / 123 (0.81%)	7 / 135 (5.19%)
occurrences all number	2	3	1	10
Eye disorders
Lacrimation increased
subjects affected / exposed	4 / 127 (3.15%)	5 / 132 (3.79%)	5 / 123 (4.07%)	7 / 135 (5.19%)
occurrences all number	4	5	6	7
Dry eye
subjects affected / exposed	4 / 127 (3.15%)	11 / 132 (8.33%)	4 / 123 (3.25%)	10 / 135 (7.41%)
occurrences all number	5	11	4	10
Gastrointestinal disorders
Stomatitis
subjects affected / exposed	4 / 127 (3.15%)	12 / 132 (9.09%)	4 / 123 (3.25%)	14 / 135 (10.37%)
occurrences all number	4	14	5	18
Abdominal pain
subjects affected / exposed	6 / 127 (4.72%)	12 / 132 (9.09%)	9 / 123 (7.32%)	15 / 135 (11.11%)
occurrences all number	7	15	11	16
Abdominal pain upper
subjects affected / exposed	7 / 127 (5.51%)	9 / 132 (6.82%)	4 / 123 (3.25%)	12 / 135 (8.89%)
occurrences all number	8	16	4	15
Constipation
subjects affected / exposed	23 / 127 (18.11%)	30 / 132 (22.73%)	19 / 123 (15.45%)	36 / 135 (26.67%)
occurrences all number	30	35	25	48
Diarrhoea
subjects affected / exposed	30 / 127 (23.62%)	40 / 132 (30.30%)	26 / 123 (21.14%)	48 / 135 (35.56%)
occurrences all number	47	63	37	85
Dry mouth
subjects affected / exposed	5 / 127 (3.94%)	7 / 132 (5.30%)	4 / 123 (3.25%)	9 / 135 (6.67%)
occurrences all number	5	7	5	10
Dyspepsia
subjects affected / exposed	9 / 127 (7.09%)	5 / 132 (3.79%)	5 / 123 (4.07%)	10 / 135 (7.41%)
occurrences all number	13	6	6	13
Gastrooesophageal reflux disease
subjects affected / exposed	4 / 127 (3.15%)	14 / 132 (10.61%)	2 / 123 (1.63%)	9 / 135 (6.67%)
occurrences all number	4	15	2	9
Nausea
subjects affected / exposed	61 / 127 (48.03%)	59 / 132 (44.70%)	55 / 123 (44.72%)	77 / 135 (57.04%)
occurrences all number	107	118	104	133
Vomiting
subjects affected / exposed	26 / 127 (20.47%)	13 / 132 (9.85%)	25 / 123 (20.33%)	27 / 135 (20.00%)
occurrences all number	39	21	42	35
Skin and subcutaneous tissue disorders
Nail disorder
subjects affected / exposed	3 / 127 (2.36%)	9 / 132 (6.82%)	10 / 123 (8.13%)	10 / 135 (7.41%)
occurrences all number	3	9	10	11
Dry skin
subjects affected / exposed	3 / 127 (2.36%)	8 / 132 (6.06%)	3 / 123 (2.44%)	7 / 135 (5.19%)
occurrences all number	4	8	3	7
Alopecia
subjects affected / exposed	83 / 127 (65.35%)	69 / 132 (52.27%)	80 / 123 (65.04%)	64 / 135 (47.41%)
occurrences all number	83	70	80	65
Rash maculo-papular
subjects affected / exposed	3 / 127 (2.36%)	8 / 132 (6.06%)	1 / 123 (0.81%)	5 / 135 (3.70%)
occurrences all number	5	8	1	7
Rash
subjects affected / exposed	18 / 127 (14.17%)	28 / 132 (21.21%)	16 / 123 (13.01%)	30 / 135 (22.22%)
occurrences all number	21	33	17	42
Pruritus
subjects affected / exposed	12 / 127 (9.45%)	18 / 132 (13.64%)	5 / 123 (4.07%)	22 / 135 (16.30%)
occurrences all number	16	23	5	24
Onycholysis
subjects affected / exposed	3 / 127 (2.36%)	8 / 132 (6.06%)	1 / 123 (0.81%)	5 / 135 (3.70%)
occurrences all number	3	8	1	5
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	7 / 127 (5.51%)	5 / 132 (3.79%)	2 / 123 (1.63%)	13 / 135 (9.63%)
occurrences all number	7	5	2	13
Hypothyroidism
subjects affected / exposed	19 / 127 (14.96%)	5 / 132 (3.79%)	8 / 123 (6.50%)	30 / 135 (22.22%)
occurrences all number	21	5	8	32
Adrenal insufficiency
subjects affected / exposed	5 / 127 (3.94%)	1 / 132 (0.76%)	0 / 123 (0.00%)	10 / 135 (7.41%)
occurrences all number	5	1	0	11
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	21 / 127 (16.54%)	42 / 132 (31.82%)	20 / 123 (16.26%)	41 / 135 (30.37%)
occurrences all number	25	48	22	52
Back pain
subjects affected / exposed	8 / 127 (6.30%)	17 / 132 (12.88%)	5 / 123 (4.07%)	16 / 135 (11.85%)
occurrences all number	8	27	6	20
Bone pain
subjects affected / exposed	3 / 127 (2.36%)	10 / 132 (7.58%)	4 / 123 (3.25%)	12 / 135 (8.89%)
occurrences all number	5	14	5	15
Myalgia
subjects affected / exposed	14 / 127 (11.02%)	22 / 132 (16.67%)	13 / 123 (10.57%)	26 / 135 (19.26%)
occurrences all number	19	29	19	29
Pain in extremity
subjects affected / exposed	7 / 127 (5.51%)	12 / 132 (9.09%)	8 / 123 (6.50%)	14 / 135 (10.37%)
occurrences all number	7	13	8	17
Infections and infestations
COVID-19
subjects affected / exposed	21 / 127 (16.54%)	29 / 132 (21.97%)	18 / 123 (14.63%)	29 / 135 (21.48%)
occurrences all number	23	29	20	31
Folliculitis
subjects affected / exposed	6 / 127 (4.72%)	5 / 132 (3.79%)	1 / 123 (0.81%)	9 / 135 (6.67%)
occurrences all number	6	5	1	10
Nasopharyngitis
subjects affected / exposed	4 / 127 (3.15%)	7 / 132 (5.30%)	1 / 123 (0.81%)	6 / 135 (4.44%)
occurrences all number	4	9	1	6
Upper respiratory tract infection
subjects affected / exposed	1 / 127 (0.79%)	5 / 132 (3.79%)	8 / 123 (6.50%)	7 / 135 (5.19%)
occurrences all number	1	5	9	7
Urinary tract infection
subjects affected / exposed	12 / 127 (9.45%)	11 / 132 (8.33%)	9 / 123 (7.32%)	8 / 135 (5.93%)
occurrences all number	13	14	10	9
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	16 / 127 (12.60%)	10 / 132 (7.58%)	13 / 123 (10.57%)	19 / 135 (14.07%)
occurrences all number	24	12	21	21
Hyperglycaemia
subjects affected / exposed	15 / 127 (11.81%)	4 / 132 (3.03%)	8 / 123 (6.50%)	13 / 135 (9.63%)
occurrences all number	19	6	8	20
Hypokalaemia
subjects affected / exposed	4 / 127 (3.15%)	6 / 132 (4.55%)	0 / 123 (0.00%)	12 / 135 (8.89%)
occurrences all number	4	9	0	14
Hyponatraemia
subjects affected / exposed	4 / 127 (3.15%)	7 / 132 (5.30%)	2 / 123 (1.63%)	3 / 135 (2.22%)
occurrences all number	6	7	3	5

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Were there any global substantial amendments to the protocol? Yes

24 Mar 2020

Study procedures update per local practice

21 May 2021

clarify expectations for eligibility, assessments, sample collection, and treatment administration.

27 Jun 2022

Details of study enrollment closure with provision for enrolled participants on treatment to continue in the study. The study objectives, endpoints, and statistical analysis have been updated and clarified.

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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Primary: Pathological Complete Response (pCR) Rate

Primary: Pathological Complete Response (pCR) Rate

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Secondary: Number of Participants with Residual Cancer Burden (RCB)

Secondary: Number of Participants with Residual Cancer Burden (RCB)

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Secondary: Number of Participants with Residual Cancer Burden (RCB) PD-L1 >=1%

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