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Immune checkpoint inhibitors and chemotherapy versus chemotherapy for early triple-negative breast cancer (Review)
Gao Y, Liu M, Li L, Zhang J, Song F, Tian J
Gao Y, Liu M, Li L, Zhang J, Song F, Tian J.
Immune checkpoint inhibitors and chemotherapy versus chemotherapy for early triple-negative breast cancer.
Cochrane Database of Systematic Reviews 2026, Issue 2. Art. No.: CD015072.
DOI: 10.1002/14651858.CD015072.pub2.
www.cochranelibrary.com
T A B L E O F C O N T E N T S
ABSTRACT	1
PLAIN LANGUAGE SUMMARY	2
SUMMARY OF FINDINGS	4
BACKGROUND	8
OBJECTIVES	9
METHODS	9
RESULTS	11
Figure 1	12
Figure 2	14
Figure 3	16
Figure 4	17
DISCUSSION	17
AUTHORS' CONCLUSIONS	19
ACKNOWLEDGEMENTS	19
REFERENCES	20
CHARACTERISTICS OF STUDIES	25
DATA AND ANALYSES	46
Analysis 1.1. Comparison 1: PD-1 or PD-L1	inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy, Outcome	46
1:		Pathological complete response	
Analysis 1.2. Comparison 1: PD-1 or PD-L1	inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy, Outcome	47
2:		Event-free survival	
Analysis 1.3. Comparison 1: PD-1 or PD-L1	inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy, Outcome	47
3:		Overall survival	
Analysis 1.4. Comparison 1: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy, Outcome 48
4:		Health-related quality of life	
Analysis 1.5. Comparison 1: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy, Outcome 48 5:	Any adverse events	
Analysis 1.6. Comparison 1: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy, Outcome 48 6:	Serious adverse events	
Analysis 1.7. Comparison 1: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy, Outcome 49 7:	Treatment-related deaths	
Analysis 2.1. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	50 subgroup analysis by type of immune checkpoint inhibitors, Outcome 1: Pathological complete response	
Analysis 2.2. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	51
subgroup analysis by type of immune checkpoint inhibitors, Outcome 2: Event-free survival	
Analysis 2.3. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	51
subgroup analysis by type of immune checkpoint inhibitors, Outcome 3: Overall survival	
Analysis 2.4. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	52
subgroup analysis by type of immune checkpoint inhibitors, Outcome 4: Health-related quality of life	
Analysis 2.5. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	52
subgroup analysis by type of immune checkpoint inhibitors, Outcome 5: Any adverse events	
Analysis 2.6. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	53
subgroup analysis by type of immune checkpoint inhibitors, Outcome 6: Serious adverse events	
Analysis 2.7. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	54
subgroup analysis by type of immune checkpoint inhibitors, Outcome 7: Treatment-related deaths	
Analysis 3.1. Comparison 3: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	55
subgroup analysis by PD-L1 status, Outcome 1: Pathological complete response	
Analysis 3.2. Comparison 3: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	56
subgroup analysis by PD-L1 status, Outcome 2: Event-free survival	
Analysis 3.3. Comparison 3: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	56
subgroup analysis by PD-L1 status, Outcome 3: Overall survival	
Analysis 4.1. Comparison 4: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	57
subgroup analysis by age, Outcome 1: Pathological complete response	
Analysis 4.2. Comparison 4: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	58
subgroup analysis by age, Outcome 2: Event-free survival	
Analysis 5.1. Comparison 5: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	59
subgroup analysis by ECOG score, Outcome 1: Pathological complete response	
Analysis 5.2. Comparison 5: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	59
subgroup analysis by ECOG score, Outcome 2: Event-free survival	
Analysis 6.1. Comparison 6: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	60
sensitivity analysis excluding studies with high risk of bias, Outcome 1: Serious adverse events	
Analysis 7.1. Comparison 7: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy –	61
sensitivity analysis excluding a study that did not report EFS definition, Outcome 1: Event-free survival	
Analysis 8.1. Comparison 8: PD-1 or PD-L1 inhibitors plus adjuvant chemotherapy vs adjuvant chemotherapy, Outcome 1: Event-	62
free survival	
Analysis 8.2. Comparison 8: PD-1 or PD-L1 inhibitors plus adjuvant chemotherapy vs adjuvant chemotherapy, Outcome 2:	62
Overall survival	
Analysis 8.3. Comparison 8: PD-1 or PD-L1 inhibitors plus adjuvant chemotherapy vs adjuvant chemotherapy, Outcome 3:	62
Health-related quality of life	
Analysis 8.4. Comparison 8: PD-1 or PD-L1 inhibitors plus adjuvant chemotherapy vs adjuvant chemotherapy, Outcome 4: Any 62 adverse events	
Analysis 8.5. Comparison 8: PD-1 or PD-L1 inhibitors plus adjuvant chemotherapy vs adjuvant chemotherapy, Outcome 5:	63 Serious adverse events	
Analysis 8.6. Comparison 8: PD-1 or PD-L1 inhibitors plus adjuvant chemotherapy vs adjuvant chemotherapy, Outcome 6:	63 Treatment-related deaths	
APPENDICES	63
HISTORY	69
CONTRIBUTIONS OF AUTHORS	69
DECLARATIONS OF INTEREST	70
SOURCES OF SUPPORT	70
DIFFERENCES BETWEEN PROTOCOL AND REVIEW	70
[Intervention Review]
Immune checkpoint inhibitors and chemotherapy versus chemotherapy for early triple-negative breast cancer
Ya Gao^1,2,3, Ming Liu^3,4, Lun Li^5, Junhua Zhang^6, Fujian Song^7, Jinhui Tian^3a
^1Department of Medical Dataology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China. ^2National Institute of Health and Medical Big Data, Jinan, China. ^3Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou City, China. ^4Lee Kong Chian School of Medicine, Nanyang Technological University, Sigapore, Singapore.
^5Department of Breast Cancer, The Second Xiangya Hospital, Central South University, Changsha, China. ^6Evidence-Based Medicine Center, Tianjin University of Traditional Chinese Medicine, Tianjin, China. ^7Norwich Medical School, University of East Anglia, Norwich, UK
^aORCID iD: https://orcid.org/0000-0002-0054-2454
Contact: Jinhui Tian, tjh996@163.com.
Editorial group: Cochrane Central Editorial Service.
Publication status and date: New, published in Issue 2, 2026.
Citation: Gao Y, Liu M, Li L, Zhang J, Song F, Tian J. Immune checkpoint inhibitors and chemotherapy versus chemotherapy for early triple-negative breast cancer. Cochrane Database of Systematic Reviews 2026, Issue 2. Art. No.: CD015072. DOI: 10.1002/14651858.CD015072.pub2.
Copyright © 2026 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
Triple-negative breast cancer (TNBC), an aggressive subtype lacking oestrogen and progesterone receptors and amplification of HER2 receptors, accounts for 12% to 17% of breast cancers. Adjuvant and neoadjuvant chemotherapy improve survival; however, 30% to 40% of early-stage TNBC cases progress to metastatic disease. Recent evidence suggests that combining immune checkpoint inhibitors (PD-1/ PD-L1 inhibitors) with chemotherapy may improve pathological complete response and event-free survival.
Objectives
To assess the benefits and harms of immune checkpoint inhibitors (PD-1 or PD-L1 inhibitors) plus chemotherapy compared with chemotherapy for people with early TNBC.
Search methods
We searched the Cochrane Breast Cancer Group Specialised Register, CENTRAL, MEDLINE, Embase, the WHO ICTRP, and ClinicalTrials.gov up to 6 November 2024. We also searched the reference lists of identified relevant trials or reviews for potentially eligible studies.
Selection criteria
Randomised controlled trials (RCTs) comparing PD-1 or PD-L1 inhibitors plus chemotherapy with chemotherapy alone in participants with early TNBC.
Data collection and analysis
Pairs of review authors independently identified studies for inclusion and performed data extraction and risk of bias assessment. Outcomes were pathological complete response, event-free survival (EFS), overall survival (OS), health-related quality of life (HRQoL), and overall rates of any adverse events and serious adverse events (SAEs). We calculated hazard ratios (HRs) for time-to-event data, risk ratios (RRs), odds ratios (ORs), or risk differences (RDs) for dichotomous outcomes, and mean differences (MDs) for continuous outcomes with corresponding 95% confidence intervals (CIs). We performed random-effects meta-analyses to summarise the evidence and evaluated the certainty of evidence using the GRADE approach.
Main results
We included seven RCTs with a total of 4341 participants. Two trials investigated PD-1 inhibitors (i.e. pembrolizumab), and five investigated PD-L1 inhibitors (i.e. durvalumab, atezolizumab) in the intervention group. Six studies used neoadjuvant chemotherapy (NACT), and one study used adjuvant chemotherapy (ACT) in the control group. The studies cover a five-year follow-up period. Two studies were at low risk of bias for all reported outcomes. The main limitation of the other trials was lack of blinding.
PD-1 or PD-L1 inhibitors plus chemotherapy versus chemotherapy alone beforebreast cancer surgery
PD-1 or PD-L1 inhibitors plus chemotherapy probably increase pathological complete response rate (RR 1.47, 95% CI 1.15 to 1.86; 6 studies, 1564 participants; moderate-certainty evidence); improve EFS (HR 0.64, 95% CI 0.52 to 0.79; 4 studies, 1789 participants; high-certainty evidence); and probably improve OS (HR 0.56, 95% CI 0.34 to 0.93; 3 studies, 1681 participants; moderate-certainty evidence) compared with chemotherapy alone. There may be little or no difference between PD-1 or PD-L1 inhibitors plus chemotherapy and chemotherapy alone in HRQoL (MD -1.49, 95% CI -3.88 to 0.91; 2 studies, 1395 participants; low-certainty evidence). PD-1 or PD-L1 inhibitors plus chemotherapy probably have little or no effect on any adverse events (OR 0.26, 95% CI 0.05 to 1.24; 3 studies, 1781 participants; moderatecertainty evidence) and treatment-related deaths (RD 0.2%, 95% CI -0.4% to 0.8%; 4 studies, 1761 participants; moderate-certainty evidence) compared with chemotherapy alone. PD-1 or PD-L1 inhibitors plus chemotherapy probably increase immune-related SAEs (OR 1.75, 95% CI 1.15 to 2.67; 5 studies, 2016 participants; moderate-certainty evidence) compared with chemotherapy alone.
PD-1 or PD-L1 inhibitors plus chemotherapy versus chemotherapy alone afterbreast cancer surgery
There may be little or no difference between PD-1 or PD-L1 inhibitors plus chemotherapy and chemotherapy alone in EFS (HR 1.11, 95% CI 0.87 to 1.42; 1 study, 2199 participants; low-certainty evidence), OS (HR 1.23, 95% CI 0.87 to 1.73; 1 study, 2199 participants; low-certainty evidence), HRQoL (MD -1.02, 95% CI -2.71 to 0.67; 1 study, 2168 participants; low-certainty evidence), any adverse events (OR 3.38, 95% CI 0.93 to 12.33; 1 study, 2177 participants; low-certainty evidence), and treatment-related deaths (RD -0.1%, 95% CI -0.4% to 0.2%; 1 study, 2177 participants; low-certainty evidence). PD-1 or PD-L1 inhibitors plus chemotherapy probably increase immune-related SAEs (OR 1.81, 95% CI 1.47 to 2.24; 1 study, 2177 participants; moderate-certainty evidence) compared to chemotherapy alone.
Authors' conclusions
Combining PD-1 or PD-L1 inhibitors with chemotherapy compared to chemotherapy alone before breast cancer surgery improves pathological response, EFS, and OS in early TNBC. In contrast, the combination of PD-1/PD-L1 inhibitors with chemotherapy after breast cancer surgery may have little to no effect on EFS and OS in early-stage TNBC when compared with chemotherapy alone. The addition of PD-1 or PD-L1 inhibitors probably increases immune-related SAEs.
P L A I N L A N G U A G E S U M M A R Y
What are the effects of combining immunotherapy (PD-1 or PD-L1 inhibitors) with chemotherapy compared with chemotherapy alone for treating early triple-negative breast cancer?
Key messages
•		For people with early triple-negative breast cancer (TNBC) (that is potentially curable breast cancer, stages 1 to 3), adding PD-1 or PD- L1 inhibitors (immunotherapy) to chemotherapy before surgery improves the chances of having no signs of cancer at the time of surgery, the length of time lived without the cancer returning, and the length of time from diagnosis or treatment start until death from any cause compared to chemotherapy alone. However, the addition of immunotherapy likely increases the risk of serious unwanted effects. Quality of life and overall unwanted effects may be similar between the two treatments.
•		There do not appear to be improvements in survival outcomes when immunotherapy is added to chemotherapy after surgery.
•		Future studies should look at how PD-1 or PD-L1 inhibitors work in different groups and focus on outcomes such as quality of life during and after treatment.
What are PD-1 or PD-L1 inhibitors?
PD-1 and PD-L1 inhibitors are medicines used in cancer treatment as part of a type of therapy called immunotherapy. They work by helping the immune system respond more effectively to cancer. Some cancer cells can avoid being noticed by the immune system by using a signal involving two proteins called PD-1 and PD-L1. PD-1 and PD-L1 inhibitors block that signal, making it easier for the immune system to find and respond to cancer cells.
Why is this important for people with early triple-negative breast cancer (TNBC)?
TNBC is an aggressive type of breast cancer that makes up about 12% to 17% of breast cancer cases. It can be more difficult to treat than other types of breast cancer. Chemotherapy, given before or after surgery, is the standard treatment, and can help improve survival. However, around 30% to 40% of people with early TNBC will still develop cancer that spreads to other parts of the body (metastasis).
New treatments are being studied that combine chemotherapy with PD-1 or PD-L1 inhibitors, which help the immune system respond to cancer. Research indicates that this combination may improve treatment results. Understanding whether this combination is safe and effective is important so that doctors and patients can make informed decisions about care.
What did we want to find out?
We wanted to know if combining PD-1 or PD-L1 inhibitors with chemotherapy works better than chemotherapy alone for people with early TNBC and if it is safe.
What did we do?
We searched for studies that compared PD-1 or PD-L1 inhibitors combined with chemotherapy and chemotherapy alone. We reviewed and summarised the results and rated our confidence in the findings based on factors such as study methods and sizes.
What did we find?
We found seven studies with a total of 4341 people. Two studies used PD-1 inhibitors (i.e. pembrolizumab) and five used PD-L1 inhibitors (i.e. durvalumab, atezolizumab). Six studies gave treatment before surgery, and one study gave treatment after surgery.
In studies comparing PD-1 or PD-L1 inhibitors combined with chemotherapy to chemotherapy alone before surgery, people who received combined therapy:
•		were more likely to have no signs of cancer at the time of surgery (about twice as many people had this result compared to those who received chemotherapy alone);
•		lived longer without cancer coming back; and
•		lived longer from the start of diagnosis or treatment until death from any cause.
There may be little or no difference between groups in quality of life. There is probably little or no difference between groups in overall unwanted effects or treatment-related deaths. Serious unwanted effects were more common and related to immunotherapy compared to chemotherapy alone.
In a single study comparing PD-1 or PD-L1 inhibitors combined with chemotherapy to chemotherapy alone after surgery, there did not appear to be improvements in survival outcomes in the combined therapy group.
What are the limitations of the evidence?
Whilst we are confident to moderately confident that adding PD-1 or PD-L1 inhibitors to chemotherapy before surgery improves survival outcomes, we have only moderate to little confidence in the results of using these medicines after surgery because the number of people in the one included study was too small to draw firm conclusions, and it is possible that people in the study knew which treatment they were getting.
How up-to-date is the evidence?
The evidence is current to 6 November 2024.
Immune checkpoint inhibitors and chemotherapy versus chemotherapy for early triple-negative breast cancer (Review)	4
Copyright © 2026 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
S U M M A R Y O F F I N D I N G S
Summary of findings 1. PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy compared to neoadjuvant chemotherapy for early triple-negative breast cancer
PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy (NACT) compared to NACT for early triple-negative breast cancer
Patient or population: people with early triple-negative breast cancer
Setting: cancer/oncologic care centres
Intervention: PD-1 or PD-L1 inhibitors plus NACT
Outcomes | Anticipated absolute effects^* (95% CI) | Relative effect (95% CI) | No. of participants (studies) | Certainty of the evidence (GRADE) | Comments
| Risk with NACT | Risk with PD-1 or PD-L1 inhibitors plus NACT | | | |

Pathological complete response
follow-up: range 5 months to 20.6 months

419 per 1000

616 per 1000 (482 to 779)

RR 1.47 (1.15 to 1.86)

1564
(6 RCTs)

⨁⨁⨁◯ Moderate^a

PD-1 or PD-L1 inhibitors plus NACT probably increase pathological complete response rate compared with NACT.

Event-free survival follow-up: range 19.8 months to 75.1 months

755 per 1000^†

835 per 1000 (801 to 864)

HR 0.64 (0.52 to 0.79)

1789
(4 RCTs)

⨁⨁⨁⨁ High

PD-1 or PD-L1 inhibitors plus NACT improve event-free survival compared with NACT.

Overall survival follow-up: range 19.8 months to 75.1 months

861 per 1000^‡

919 per 1000 (869 to 950)

HR 0.56 (0.34 to 0.93)

1681
(3 RCTs)

⨁⨁⨁◯ Moderate^a

PD-1 or PD-L1 inhibitors plus NACT probably improve overall survival compared with NACT.

Health-related quality of life follow-up: 5 months to 24 months

The mean health-related quality of life was -5.84.

MD 1.49 lower (3.88 lower to 0.91 higher)

_-

1395
(2 RCTs)

⨁⨁◯◯ Low^b

There may be little or no difference between PD-1 or PD-L1 inhibitors plus NACT and NACT in health-related quality of life.

Any adverse events follow-up: range 7.8 months to 39.1 months

999 per 1000

995 per 1000 (972 to 999)

OR 0.26 (0.05 to 1.24)

1781
(3 RCTs)

⨁⨁⨁◯ Moderate^c

There is probably little or no difference between PD-1 or PD-L1 inhibitors plus NACT and NACT in any adverse events.

Comparison: NACT

Immune checkpoint inhibitors and chemotherapy versus chemotherapy for early triple-negative breast cancer (Review)	5
Copyright © 2026 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Serious adverse events follow-up: range 5 months to 39.1 months

188 per 1000

288 per 1000 (210 to 382)

OR 1.75 (1.15 to 2.67)

2016
(5 RCTs)

⨁⨁⨁◯ Moderate^a

PD-1 or PD-L1 inhibitors plus NACT probably increase serious adverse events compared with NACT.

Treatment-related deaths follow-up: range 5 months to 39.1 months

1 per 1000

3 per 1000
(0 to 9)

-

1761
(4 RCTs)

⨁⨁⨁◯ Moderate^c

There is probably little or no difference between PD-1 or PD-L1 inhibitors plus NACT and NACT in treatment-related deaths.

Outcomes | Anticipated absolute effects^* (95% CI) | Relative effect (95% CI) | No. of participants (studies) | Certainty of the evidence (GRADE) | Comments

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; HR: hazard ratio; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^†Baseline risk in the control arm was based on estimates of patients free from events of disease recurrence, progression, or death at three years from three studies (GeparNuevo; I-SPY2; KEYNOTE-522).
^‡Baseline risk in the control arm was based on estimates of patients alive at three years from two studies (GeparNuevo; KEYNOTE-522).
^aDowngraded one level for inconsistency due to the limited overlap of CIs in point estimates.
^bDowngraded two levels for imprecision due to the 95% CI crossing the null effect and wide CI.
^cDowngraded one level for imprecision due to the 95% CI crossing the null effect.
Summary of findings 2. PD-1 or PD-L1 inhibitors plus adjuvant chemotherapy compared to adjuvant chemotherapy for early triple-negative breast cancer
PD-1 or PD-L1 inhibitors plus adjuvant chemotherapy (ACT) compared to ACT for early triple-negative breast cancer
Patient or population: people with early triple-negative breast cancer
Setting: cancer/oncologic care centres
Intervention: PD-1 or PD-L1 inhibitors plus ACT
Comparison: ACT
Immune checkpoint inhibitors and chemotherapy versus chemotherapy for early triple-negative breast cancer (Review)	6
Copyright © 2026 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
| Risk with ACT | Risk with PD-1 or PD-L1 inhibitors plus ACT |

Event-free survival follow-up: median 32 months

864 per 1000

850 per 1000 (813 to881)

HR 1.11 (0.87 to 1.42)

2199
(1 RCT)

⨁⨁◯◯ Low^a,b

There may be little or no difference between PD-1 or PD-L1 inhibitors plus ACT and ACT in event-free survival at 3 years.

Overall survival follow-up: median 32 months

937 per 1000

923 per 1000 (894 to 945)

HR 1.23 (0.87 to 1.73)

2199
(1 RCT)

⨁⨁◯◯ Low^a,b

There may be little or no difference between PD-1 or PD-L1 inhibitors plus ACT and ACT in overall survival at 3 years.

Health-related quality of life
follow-up: mean 24 months

The mean health-related quality of life was 1.21

MD 1.02 lower (2.71 lower to 0.67 higher)

-

2168
(1 RCT)

⨁⨁◯◯ Low^b,c

There may be little or no difference between PD-1 or PD-L1 inhibitors plus ACT and ACT in health-related quality of life.

Any adverse events follow-up: median 32 months

991 per 1000

997 per 1000 (990 to 999)

OR 3.38
(0.93 to 12.33)

2177
(1 RCT)

⨁⨁◯◯ Low^a,b

There may be little or no difference between PD-1 or PD-L1 inhibitors plus ACT and ACT in any adverse events.

Serious adverse
events follow-up: median 32 months

160 per 1000

256 per 1000
(219 to 299)

OR 1.81 (1.47 to 2.24)

2177
(1 RCT)

⨁⨁⨁◯ Moderate^a

PD-1 or PD-L1 inhibitors plus ACT probably increase serious adverse events compared with ACT.

Treatment-related deaths
follow-up: median 32 months

1 per 1000

0 per 1000 (0 to 3)

-

2177
(1 RCT)

⨁⨁◯◯ Low^a,b

There may be little or no difference between PD-1 or PD-L1 inhibitors plus ACT and ACT in treatment-related deaths.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; HR: hazard ratio; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level for risk of bias due to early trial termination.
^bDowngraded one level for imprecision due to the 95% CI crossing the null effect.

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B A C K G R O U N D
Description of the condition
Breast cancer is the most common type of cancer and the leading cause of cancer deaths in women worldwide (Sung 2021). In 2020, there were approximately 2.3 million new cases of breast cancer and 683,100 deaths (Sung 2021). Newly diagnosed breast cancers should be tested for oestrogen receptor (ER) and progesterone receptor (PR) expression as well as overexpression of erb-b2 receptor tyrosine kinase 2 (ERBB2), also known as HER2. This information is critical for therapeutic and prognostic purposes. Breast cancer can be characterised into different subtypes according to whether or not they express ER, PR, and HER2 (O'Brien 2010; Parise 2009). Triple-negative breast cancer (TNBC) is defined by the lack of expression of the ER, PR, and HER2 on cancer cells (Mittendorf 2020). Approximately 12% to 17% of breast cancers are TNBC, and early-stage TNBC accounts for 10% to 20% of new diagnoses of early breast cancer (Foulkes 2010). TNBC tends to behave more aggressively than other types of breast cancer and is associated with higher mortality and a higher likelihood of recurrence (Hudis 2011).
In general, people with early-stage breast cancer undergo primary surgery (lumpectomy or mastectomy) of the breast and regional nodes with or without radiation therapy. However, some people with early-stage invasive breast cancer (particularly those with TNBC) may be treated with preoperative (or neoadjuvant) therapy first, followed by surgery. Chemotherapy remains the standard of care for primary TNBC (Loibl 2019).
Most international guidelines recommend sequential use of a taxane and anthracycline plus cyclophosphamide as the optimal chemotherapy regimen for early TNBC (Cardoso 2019; NCCN 2020). Multiagent chemotherapy regimens have shown benefits in improving disease-specific and overall survival outcomes when provided as neoadjuvant or adjuvant (postoperative) therapy for early TNBC (Budd 2015; Burstein 2019; Gianni 2018; Untch 2016). However, the five-year metastasis-free survival rate is about 70%, and about 30% to 40% of people will develop metastatic disease (Budd 2015; Masuda 2017; Sharma 2017). Recently, immune checkpoint inhibitors have been used to treat early-stage TNBC and have been shown to improve pathological complete response and event-free survival (Mittendorf 2020; Schmid 2020; Schmid 2022).
Description of the intervention
Immune checkpoints are molecules that modulate the immune response in peripheral tissues and are activated to prevent tissue damage (Pardoll 2012). The programmed cell death ligand 1 or 2 (PD-L1, PD-L2) and programmed cell death protein 1 (PD-1) are immune checkpoint proteins found on cells that help keep this immune response in check. When the PD-L1 binds to PD-1, this partnership sends a signal that inhibits immune cells from killing their partner cell (Collin 2016; Okazaki 2001; Topalian 2013; Walankiewicz 2018). This is one mechanism by which cancer cells can evade the immune response. Immune checkpoint inhibitors work by blocking the binding of these two proteins and reactivating the immune response.
Many immune checkpoint inhibitors have been used to prolong survival in lung cancer (Chae 2018), Hodgkin's lymphoma (Ansell 2015), melanomas (Zaretsky 2016), and renal cell carcinoma (Motzer 2015). Immune checkpoint inhibitors have been shown to have antitumour activity and a range of low- grade toxic effects in people with metastatic TNBC (Adams 2019a; Adams 2019b; Nanda 2016). Types of immune checkpoint inhibitors include pembrolizumab, nivolumab, durvalumab, and atezolizumab. Recently, the combination of PD-1 or PD-L1 inhibitors and chemotherapy has been used for treating early- stage TNBC. A double-blind, randomised, phase III trial reported that pembrolizumab plus neoadjuvant chemotherapy resulted in a significantly higher percentage of pathological complete responses (64.8% versus 51.2%) than placebo plus neoadjuvant chemotherapy (Schmid 2020). Another randomised controlled trial showed that early-stage TNBC treated with atezolizumab plus chemotherapy had higher pathological complete responses but higher treatment-related serious adverse events compared with placebo plus chemotherapy (Mittendorf 2020).
How the intervention might work
PD-1 protein is expressed on various cells such as NK cells, B cells, dendritic cells, antigen-presenting cells, activated CD4+ T cells and CD8+ T cells, and monocytes (Dinesh 2010; Walankiewicz 2018). The function of PD-1 is to inhibit the activation of T cells and B cells, which is a normal mechanism of the immune system. However, the tumour microenvironment will induce the T cells to highly express PD-1 molecules, and the tumour cells will highly express PD-1 ligands (PD-L1 and PD-L2). This leads to the continuous activation of the PD-1 pathway in the tumour microenvironment where T cell function is inhibited and T cells are unable to kill tumour cells.
PD-1 inhibitors can block this pathway and partially restore the function of T cells so that these cells can continue to kill tumour cells (Gaynor 2022; Pilipow 2021). In addition, PD-L1 inhibitors can block the interaction of immune checkpoint proteins and play a similar role to PD-1 inhibitors. PD-1 inhibitors and PD-L1 inhibitors have similar mechanisms: they can block the binding of PD-1 and PD-L1, upregulate the growth and proliferation of T cells, enhance T cells’ recognition of tumour cells, and activate T cell attack and killing functions to achieve antitumour effects (Gaynor 2022). Furthermore, chemotherapy increases the release of tumour-specific antigens on cancer cells, and immune checkpoint inhibitors can subsequently enhance the immune response against cancer cells (Farkona 2016). In summary, chemotherapy may work synergistically with immune checkpoint inhibitors (Galluzzi 2015; Spigel 2013).
Why it is important to do this review
Early TNBC is associated with an increased risk of recurrence compared to other breast cancers. Achieving a pathological complete response after neoadjuvant chemotherapy is strongly associated with improved survival outcomes, whilst the presence of residual disease (i.e. a high residual cancer burden score) is significantly associated with worse event-free survival (Yau 2022).
Immune checkpoint inhibitors plus chemotherapy has recently shown potential to improve pathological complete response or event-free survival in people with early-stage TNBC. However, it is unclear whether the combination of immune-targeted therapy and chemotherapy regimen leads to higher efficacy at the cost of increased toxicity, and whether treatment effects vary across different subgroups of patients (e.g. PD-L1-positive population or -negative population) and types of agents (e.g. nivolumab, pembrolizumab, durvalumab). It is therefore important to conduct a systematic review to summarise all the evidence on the effects of immune checkpoint inhibitors (i.e. PD-1 inhibitors or PD-L1 inhibitors) plus chemotherapy for early TNBC and report toxicities, quality of life, and treatment benefits, which will benefit physicians and people with early TNBC.
O B J E C T I V E S
To assess the benefits and harms of immune checkpoint inhibitors (PD-1 or PD-L1 inhibitors) plus chemotherapy compared with chemotherapy for people with early triple-negative breast cancer.
M E T H O D S
Criteria for considering studies for this review
Types of studies
We included parallel, cross-over, cluster-, or quasi- (e.g. randomised by day of week), phase II or III randomised controlled trials (RCTs) with or without blinding. To limit publication bias, we also incorporated unpublished online data if sufficient data were provided for analysis and risk of bias assessment.
Types of participants
Women or men aged 18 years or older and histologically confirmed TNBC in all foci (by central assessment of negative HER2, ER, and PR status according to American Society of Clinical Oncology/College of American Pathologists guidelines). We included people with potentially curable breast cancer (stages 1 to 3). We included trials where bilateral or multifocal primary tumours and inflammatory breast cancers were eligible for enrolment.
We excluded studies where people received treatment for recurrent breast cancer or residual disease after prior therapy.
Types of interventions
Interventions: PD-1 inhibitors (e.g. nivolumab, pembrolizumab/ lambrolizumab, pidilizumab, or tislelizumab) or PD-L1 inhibitors (e.g. atezolizumab, avelumab, or durvalumab) plus chemotherapy. Given that our review focused on PD-1 inhibitors and PD-L1 inhibitors, we excluded interventions of CTLA-4 inhibitors plus chemotherapy or PD-1 inhibitors/PD-L1 inhibitors plus CTLA-4 inhibitors plus chemotherapy.
Comparator: chemotherapy or chemotherapy plus placebo. We did not limit the chemotherapy regimen.
We included the following pair-wise comparisons:
•		PD-1 inhibitors or PD-L1 inhibitors plus chemotherapy versus chemotherapy;
•		PD-1 inhibitors or PD-L1 inhibitors plus chemotherapy versus chemotherapy plus placebo.
Types of outcome measures
Primary outcomes
•		Pathological complete response: defined as no invasive tumour residuals in the breast and in lymph nodes.
•		Event-free survival (EFS): time from randomisation to disease recurrence, progression, or death from any cause.
Secondary outcomes
•		Overall survival (OS): time from randomisation to death from any cause.
•		Health-related quality of life (HRQoL), measured by a validated scale.
•		Overall rates of any adverse events and serious adverse events (SAEs): severity level assessed according to the National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-CTCAE) (NCI-CTCAE 2010), including the percentage of treatment-related deaths, as well as (if separate data are available) immune-related adverse events (irAEs).
Search methods for identification of studies
Electronic searches
We searched the following databases and trial registries.
•		The Cochrane Breast Cancer Group (CBCG) Specialised Register. Details of the search strategies used by the Group for the identification of studies and the procedure used to code references are outlined in the Group's module. Trials with the keywords 'immunotherapy', 'immune checkpoint inhibitors', 'PD-1 Inhibitor', 'PD-L1 Inhibitor', 'Programmed Cell Death Protein 1 Inhibitor', 'Programmed Death-Ligand 1 Inhibitor', 'nivolumab', 'pembrolizumab', 'lambrolizumab', 'pidilizumab', 'tislelizumab', 'atezolizumab', 'avelumab', 'durvalumab', 'cemiplimab', 'dostarlimab', 'spartalizumab' or 'toripalimab' were extracted and considered for inclusion in the review.
•		The Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library; Issue 10, 2024) (searched 6 November 2024). See Appendix 1.
•		MEDLINE (via OvidSP) from 2005 (immune checkpoint inhibitors were not available, even in clinical trials, before 2005) to 6 November 2024. See Appendix 2.
•		Embase (via OvidSP) from 2005 to 6 November 2024. See Appendix 3.
•		World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (apps.who.int/trialsearch/Default.aspx) for all prospectively registered and ongoing trials (searched 6 November 2024). See Appendix 4.
•		ClinicalTrials.gov (clinicaltrials.gov/) (searched 6 November 2024). See Appendix 5.
We did not apply any restrictions on language.
Searching other resources
Bibliographic searching: we screened the reference lists of identified relevant trials or reviews. We obtained a copy of the full article for each reference reporting a potentially eligible trial.
Conference proceedings: we searched the Embase database available via OvidSP for the conference proceedings of:
•		American Association of Cancer Research (AACR); and
•		European Society of Medical Oncology (ESMO).
Data collection and analysis
Selection of studies
Two review authors (YG, ML) independently screened the titles and abstracts of all references identified by the search strategy. The same two review authors further evaluated the full text of each record deemed potentially eligible to determine study eligibility. Any disagreements were resolved by consensus or adjudication from a third review author.
We recorded the selection process in the PRISMA flow diagram. In addition, we listed the reasons for excluding key full-text articles in the Characteristics of excluded studies table. We applied no language restrictions.
Data extraction and management
Two review authors (YG, ML) independently extracted data from each eligible trial. Any discrepancies were resolved by consensus or adjudication from another review author (JT). When we encountered multiple publications for the same trial, we chose the first publication reporting the primary endpoint in this review as a study identifier (study ID).
We extracted the following data.
•		Study details: study design, randomisation protocol, number of study centres, location, study setting, date of study, duration of study, duration of follow-up period.
•		Characteristics of participants: inclusion and exclusion criteria, sample size (total and by arm), age, sex, stage, severity of condition, diagnostic criteria, comorbidities, previous treatments, histology, PD-L1 expression.
•		Characteristics of interventions: details of interventions, e.g. choice and dosing schedule of immune checkpoint inhibitors and chemotherapies.
•		Outcomes: primary and secondary outcomes with definitions and time points.
•		Results: number of participants allocated to each group, the total number analysed for each outcome, summary data for each group, and whether analyses were performed by intention- to-treat (ITT) or per-protocol methods.
•		Miscellaneous: funding source.
Assessment of risk of bias in included studies
Two review authors (YG, ML) independently assessed risk of bias in the included studies using the Cochrane RoB 1 tool (Higgins 2011). Any disagreements were resolved by discussion with a third review author (JT). We assessed risk of bias for the blinding of participants and personnel and blinding of the outcome assessment domains at the outcome level. Overall, we assessed the following domains.
•		Random sequence generation
•		Allocation concealment
•		Blinding of participants and personnel
•		Blinding of outcome assessment
•		Incomplete outcome data
•		Selective outcome reporting
•		Other potential sources of bias
We assigned a rating of low, high, or unclear risk of bias for each risk of bias domain for each included study. We reported the results in a risk of bias summary. When interpreting treatment effects and meta-analyses, we took into account the risk of bias for the studies that contributed to that outcome.
Measures of treatment effect
We analysed time-to-event outcomes (EFS and OS) using the hazard ratio (HR) and corresponding 95% confidence intervals (CIs). We extracted HR and associated variances directly from the trial publications. If these were not reported, we attempted to estimate the log (HR) and its standard error indirectly using the methods described by Parmar 1998 and Tierney 2007.
We used risk ratio (RR) and corresponding 95% CIs to express the dichotomous outcome of pathological complete response; odds ratio (OR) for overall rates of any adverse events and SAEs; and risk differences (RDs) for treatment-related deaths.
We planned to use standardised mean differences (SMDs) for continuous outcomes (HRQoL). However, since eligible studies reported HRQoL measured using the same scale (i.e. QLQ-C30), we used mean differences (MDs) with 95% CIs.
For the purposes of data extraction, we gave preference to data derived from ITT analysis than from per-protocol analysis.
Unit of analysis issues
For studies comparing two or more intervention groups and the same control group, we planned to halve the control group to allow a comparison with each of the two intervention groups. Similarly, for studies comparing one intervention group to two or more control groups, we planned to divide the intervention group as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). However, we did not encounter these issues.
Dealing with missing data
We performed analyses on an ITT basis. We investigated attrition rates (e.g. dropouts, losses to follow-up, and withdrawals), and critically appraised issues of missing data. Regarding trials for which we were unable to retrieve missing data, we planned to perform sensitivity analyses by excluding trials assessed as having a high risk of attrition bias.
Assessment of heterogeneity
We assessed heterogeneity using the Chi^2 test and the I^2 statistic (Cochran 1954; Higgins 2003). For the I^2 statistic, a value of 25% to 50% might represent mild heterogeneity, 50% to 75% moderate heterogeneity, and 75% considerable heterogeneity (Higgins 2021). If we identified heterogeneity between trials, we explored possible causes using subgroup analyses and sensitivity analyses.
In the case of clinical heterogeneity, we would not conduct metaanalysis but would instead narratively describe the results of each study as outlined in Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (McKenzie 2019). We used the random-effects model to perform meta-analyses.
Assessment of reporting biases
In future updates, if at least 10 studies are included in a metaanalysis, we will explore reporting biases by using funnel plot asymmetry (Higgins 2021).
Where possible, we compared eligible trials and corresponding protocols to assess outcome reporting bias.
Data synthesis
We performed meta-analyses with data based on ITT analysis. We synthesised studies investigating adjuvant and neoadjuvant chemotherapy separately. We used the DerSimonian and Laird random-effects model (DerSimonian 1986) with the generic inverse variance method for meta-analyses.
•		For the dichotomous outcome of pathological complete response, we estimated pooled RRs and 95% CIs; for adverse events, we estimated pooled ORs. For eligible trials with zero events in only a single arm, we planned to use the continuity correction method; for eligible trials with zero events in double arms, we estimated RDs.
•		For continuous outcomes, we estimated pooled MDs and 95% CIs.
•		For time-to-event data, we pooled HRs and 95% CIs.
We performed meta-analyses using RevMan (RevMan 2025), following the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).
Subgroup analysis and investigation of heterogeneity
If sufficient data were available, we considered the following factors for subgroup analyses.
•		PD-1 inhibitors or PD-L1 inhibitors
•		PD-L1 status: positive versus negative
•		Age < 65 or ≥ 65 years
•		Eastern Cooperative Oncology Group (ECOG) score 0 or 1
•		Duration of intervention
Sensitivity analysis
In the case of sufficient data, we performed sensitivity analyses to assess the robustness of the results. We planned to conduct sensitivity analyses by excluding studies:
•		at high risk of bias (i.e. at high risk for at least one risk of bias domain);
•		with unpublished data;
•		with missing data;
•		where there were different definitions of EFS across studies;
•		with cross-over, cluster-RCT, or quasi-RCT design.
Summary of findings and assessment of the certainty of the evidence
Two review authors (YG, ML) rated the certainty of the evidence for the outcomes listed below using the five GRADE considerations (risk of bias, inconsistency, imprecision, indirectness, and publication bias) (Guyatt 2008; Zeng 2021). We rated the overall certainty of evidence as high, moderate, low, or very low.
We included the following outcomes in the summary of findings tables:
•		pathological complete response;
•		EFS;
•		OS;
•		HRQoL;
•		overall rates of any adverse events;
•		overall rates of SAEs;
•		treatment-related deaths.
We used GRADEpro GDT software to develop the summary of findings tables (GRADEpro GDT).
R E S U L T S
Description of studies
See Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; and Characteristics of ongoing studies.
Results of the search
Figure 1 shows details of the study selection. Our search of the electronic databases, followed by examination of the included studies’ reference lists, yielded 2422 records. After removing 473 duplicate records, we screened 1949 titles and abstracts, then 48 records as full text. We identified one ongoing study (NCT04301739) and one study awaiting classification (NCT03356860), and excluded 29 records. We included seven studies (17 records) in the meta-analysis (ALEXANDRA/IMpassion030; GeparNuevo; I-SPY2; IMpassion031; KEYNOTE-522; NCI 10013; NeoTRIP).

Figure 1. Study flow diagram.

1949 records screened
48 full-text articles assessed for eligibility
7 studies (17 records) included in qualitative synthesis
7 studies (17 records) included in quantitative synthesis

1901 records
excluded
29 full-text articles excluded, with reasons:
•		13 not RCT
•		2 registered record of published trial without reported result
•		4 not early TNBC
•		4 no eligible comparison
•		3 previously treated with neoadjuvant
chemotherapy
•		1 not PD-1/PD-L1
•		1 wrong outcome
•		1 no result
1 ongoing study
1 study awaiting classification

Figure 1. (Continued)

in quantitative
synthesis (meta-analysis)

Included studies
We identified six trials comparing PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy (NACT) versus NACT (GeparNuevo; I-SPY2; IMpassion031; KEYNOTE-522; NCI 10013; NeoTRIP), and one trial comparing PD-1 or PD-L1 inhibitors plus adjuvant chemotherapy (ACT) versus ACT (ALEXANDRA/IMpassion030).
PD-1 or PD-L1 inhibitors plus NACT versus NACT
Design
All six studies were parallel RCTs. Three studies were phase II trials (GeparNuevo; I-SPY2; NCI 10013); three were phase III trials (IMpassion031; KEYNOTE-522; NeoTRIP); three were double-blind RCTs (GeparNuevo; IMpassion031; KEYNOTE-522); and three were open-label RCTs (I-SPY2; NCI 10013; NeoTRIP).
Setting
All studies were multicentre studies. One study enrolled participants from Germany (GeparNuevo), two from the USA (I- SPY2; NCI 10013), one from Austria, Germany, Ireland, Italy, Russia, Spain, and China (NeoTRIP), one from 13 countries (IMpassion031), and one from 21 countries (KEYNOTE-522).
Participants
The six trials enrolled a total of 2142 participants (GeparNuevo; I- SPY2; IMpassion031; KEYNOTE-522; NCI 10013; NeoTRIP), with the sample size ranging from 67 to 1174. The median age of participants was between 47 and 54 years. All studies focused on participants aged 18 years or older with early-stage, previously untreated TNBC.
Interventions
Two trials investigated PD-1 inhibitors (I-SPY2; KEYNOTE-522), and four investigated PD-L1 inhibitors (GeparNuevo; IMpassion031; NCI 10013; NeoTRIP) in the intervention group. Two trials compared pembrolizumab plus NACT versus NACT (I-SPY2; KEYNOTE-522); one trial compared durvalumab plus NACT versus NACT (GeparNuevo); and three trials compared atezolizumab plus NACT versus NACT (IMpassion031; NCI 10013; NeoTRIP). NACT usually included paclitaxel/nab-paclitaxel, doxorubicin, carboplatin, epirubicin, and cyclophosphamide.
Outcomes
All six trials reported pathological complete response, which they defined as no invasive tumour residuals in breast and lymph nodes (GeparNuevo; IMpassion031; I-SPY2; KEYNOTE-522; NCI 10013; NeoTRIP). Four trials reported EFS (GeparNuevo; IMpassion031; I-SPY2; KEYNOTE-522). Three trials had similar definitions of EFS: time from randomisation to disease recurrence, progression, or death from any cause (GeparNuevo; IMpassion031; KEYNOTE-522). One trial did not report a definition of EFS (I- SPY2). Three trials reported OS, which they defined identically as the time from randomisation to death from any cause (GeparNuevo; IMpassion031; KEYNOTE-522). Two trials reported HRQoL (IMpassion031; KEYNOTE-522). Three trials reported any adverse events (IMpassion031; KEYNOTE-522; NeoTRIP); five trials reported SAEs (GeparNuevo; IMpassion031; KEYNOTE-522; NCI 10013; NeoTRIP); and four trials reported treatment-related deaths (I-SPY2; KEYNOTE-522; NCI 10013; NeoTRIP).
PD-1 or PD-L1 inhibitors plus ACT versus ACT
Design
The one study comparing PD-L1 inhibitor plus ACT versus ACT was a parallel RCT (ALEXANDRA/IMpassion030). It was a phase III trial and an open-label RCT.
Setting
ALEXANDRA/IMpassion030 was a multicentre study and enrolled participants from 29 countries.
Participants
ALEXANDRA/IMpassion030 enrolled a total of 2199 participants. The median age of participants was 53 years in both the atezolizumab plus chemotherapy group and the chemotherapy group. The study focused on participants aged 18 years or older with non-metastatic operable stage II or III TNBC, who had been adequately excised (breast-conserving surgery or mastectomy).
Interventions
ALEXANDRA/IMpassion030 investigated a PD-L1 inhibitor (atezolizumab) plus ACT versus ACT. The ACT included paclitaxel, doxorubicin or epirubicin, and cyclophosphamide.
Outcomes
ALEXANDRA/IMpassion030 reported invasive disease-free survival (iDFS) as the primary outcome, defined as the interval between randomisation and the first ipsilateral invasive breast tumour recurrence, ipsilateral local-regional invasive breast cancer recurrence, ipsilateral second primary invasive breast cancer, contralateral invasive breast cancer, distant recurrence, or death from any cause. Secondary outcomes included OS (time from randomisation to the date of death from any cause), HRQoL (measured using the global health status (GHS)/QoL scale of the EORTC QLQ-30), any adverse events, SAEs, and treatment-related deaths.
Excluded studies
We excluded 29 studies. Thirteen studies were not RCTs; two were trial registrations without results; four did not focus on early TNBC; four did not include an eligible comparison; three focused on TNBC participants who had been previously treated with NACT;
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Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias): Pathological complete response
Blinding of participants and personnel (performance bias): Event-free survival
Blinding of participants and personnel (performance bias): Overall survival
Blinding of participants and personnel (performance bias): Health-related quality of life
Blinding of participants and personnel (performance bias): Any adverse events
Blinding of participants and personnel (performance bias): Serious adverse events
Blinding of participants and personnel (performance bias): Treatment-related deaths
Blinding of outcome assessment (detection bias): Pathological complete response
Blinding of outcome assessment (detection bias): Event-free survival
Blinding of outcome assessment (detection bias): Overall survival
Blinding of outcome assessment (detection bias): Health-related quality of life
Blinding of outcome assessment (detection bias): Any adverse events
Blinding of outcome assessment (detection bias): Serious adverse events
Blinding of outcome assessment (detection bias): Treatment-related deaths
Incomplete outcome data (attrition bias): All outcomes
Selective reporting (reporting bias)
Other bias
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Blinding
For pathological complete response, three trials were double-blind trials (GeparNuevo; IMpassion031; KEYNOTE-522), and three were open-label trials (I-SPY2; NCI 10013; NeoTRIP). As the pathologist evaluated the pathological complete response, blinding of participants and personnel (performance bias) and outcome assessment (detection bias) were generally not a significant concern. We therefore assessed these six trials as at low risk of performance and detection bias.
As EFS and OS were objective outcomes, we rated five studies as at low risk of performance and detection bias for EFS (ALEXANDRA/ IMpassion030; GeparNuevo; I-SPY2; IMpassion031; KEYNOTE-522), and four studies as at low risk of performance and detection bias for OS (ALEXANDRA/IMpassion030; GeparNuevo; IMpassion031; KEYNOTE-522).
We rated two trials that reported HRQoL as at low risk of performance bias (IMpassion031; KEYNOTE-522), as they were both double-blind trials. We rated these two studies as at unclear risk of detection bias as they did not provide details on the blinding of outcome assessors (IMpassion031; KEYNOTE-522). We rated one trial that reported HRQoL as at high risk of performance and detection bias (ALEXANDRA/IMpassion030), as it was an open-label trial.
Of four trials that reported any adverse events, two double-blind trials were at low risk of bias for blinding of participants and personnel (IMpassion031; KEYNOTE-522). Two studies reported that adverse events were categorised according to the NCI- CTCAE version 4.0 or 5.0 (ALEXANDRA/IMpassion030; NeoTRIP). NCI-CTCAE provides a standardised and objective system for classifying and grading adverse events, and the use of such a well-defined and objective tool reduces the potential for bias in reporting and assessing adverse events. We therefore rated these studies as at low risk of bias for blinding of participants and personnel. Regarding blinding of outcome assessment, one study reported that an independent data monitoring committee reviewed unmasked safety and study conduct data every six months (IMpassion031); one study reported that an external, independent data monitoring committee oversaw the trial, periodically assessed safety, and assessed efficacy at prespecified interim analyses (KEYNOTE-522); and two studies reported that adverse events were categorised according to the NCI-CTCAE version 4.0 or 5.0 (NeoTRIP). We therefore judged these four trials to be at low risk of detection bias (ALEXANDRA/IMpassion030; IMpassion031; KEYNOTE-522; NeoTRIP).
Regarding SAEs, five trials used NCI-CTCAE to capture information (ALEXANDRA/IMpassion030; GeparNuevo; IMpassion031; KEYNOTE-522; NeoTRIP). We classified these five trials as having a low risk of bias for blinding of participants and personnel and outcome assessment. Conversely, one trial followed an open-label design and did not report the use of CTCAE (NCI 10013). Consequently, we rated this trial as having a high risk of bias for blinding of participants and personnel and outcome assessment.
We rated five trials that reported treatment-related deaths as at low risk of bias for blinding of participants and personnel and outcome assessment (ALEXANDRA/IMpassion030; I-SPY2; KEYNOTE-522; NCI 10013; NeoTRIP).
Incomplete outcome data
Because the primary analysis was done on the ITT population with accountability for attrition, or because the number of participants missing from follow-up was low (dropout rates below 10%), we judged all the included studies to be at low risk of attrition bias.
Selective reporting
We judged six studies that prespecified all reported outcomes in their trial registries to be low risk of selective outcome reporting (ALEXANDRA/IMpassion030; GeparNuevo; I-SPY2; IMpassion031; KEYNOTE-522; NeoTRIP). One study only prespecified some outcomes in their trial registry; we judged this trial to be unclear risk of selective outcome reporting (NCI 10013).
Other potential sources of bias
We identified no other sources of bias for all seven trials (ALEXANDRA/IMpassion030; GeparNuevo; I-SPY2; IMpassion031; KEYNOTE-522; NCI 10013; NeoTRIP), and therefore considered them to be at low risk of bias.
Effects of interventions
See: Summary of findings 1 PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy compared to neoadjuvant chemotherapy for early triple-negative breast cancer; Summary of findings 2 PD-1 or PD-L1 inhibitors plus adjuvant chemotherapy compared to adjuvant chemotherapy for early triple-negative breast cancer
PD-1 or PD-L1 inhibitors plus NACT versus NACT
See Summary of findings 1.
Primary outcomes
Pathological complete response
Six trials with 1564 participants reported data on pathological complete response (GeparNuevo; I-SPY2; IMpassion031; KEYNOTE-522; NCI 10013; NeoTRIP). PD-1 or PD-L1 inhibitors plus NACT probably increase pathological complete response rate (RR 1.47, 95% CI 1.15 to 1.86; 6 studies, 1564 participants; moderatecertainty evidence; Analysis 1.1) compared with NACT alone. We downgraded the certainty of evidence to moderate due to substantial heterogeneity (Chi^2 = 19.51, I^2 = 74%) and limited overlap of CIs in point estimates.
Subgroup analyses did not suggest apparent subgroup effects according to the type of immune checkpoint inhibitors (Analysis 2.1), PD-L1 status (Analysis 3.1), age (Analysis 4.1), and ECOG score (Analysis 5.1). No studies were at high risk of bias for this outcome, so a sensitivity analysis was not performed.
Event-free survival
Four trials with 1789 participants provided high-certainty evidence that PD-1 or PD-L1 inhibitors plus NACT improve EFS (HR 0.64, 95% CI 0.52 to 0.79; 4 studies, 1789 participants; high-certainty evidence; Analysis 1.2) compared with NACT alone (GeparNuevo; I- SPY2; IMpassion031; KEYNOTE-522).
Subgroup analyses did not suggest apparent subgroup effects according to the type of immune checkpoint inhibitors (Analysis 2.2), PD-L1 status (Analysis 3.2), age (Analysis 4.2), and ECOG score

(Analysis 5.2). Sensitivity analysis excluding I-SPY2, which did not report the definition of EFS, also showed a similar result (HR 0.64, 95% CI 0.52 to 0.80; Chi^2 = 0.94, I^2 =0%; Analysis 7.1).
Secondary outcomes
Overall survival
Three trials with 1681 participants reported OS. PD-1 or PD-L1 inhibitors plus NACT probably improve OS (HR 0.56, 95% CI 0.34 to 0.93; Chi^2 = 3.10, I^2 = 36%; 3 studies, 1681 participants; moderatecertainty evidence; Analysis 1.3) compared with NACT alone (GeparNuevo; IMpassion031; KEYNOTE-522). We downgraded the certainty of evidence to moderate due to limited overlap of CIs in point estimates.
Subgroup analyses by type of immune checkpoint inhibitors (Analysis 2.3) and PD-L1 status (Analysis 3.3) did not reveal any subgroup effects. All studies were at low risk of bias for this outcome, so a sensitivity analysis was not performed.
Health-related quality of life
Two trials with 1395 participants provided data on HRQoL as measured with the global health status (GHS)/QoL scale of the EORTC QLG Core Questionnaire (EORTC QLQ-C30) (IMpassion031; KEYNOTE-522). IMpassion031 reported data from baseline to 24 months, and KEYNOTE-522 reported data from baseline to 21 weeks. There may be little or no difference between PD-1 or PD-L1 inhibitors plus NACT and NACT in HRQoL (MD -1.49, 95% CI -3.88 to 0.91; Chi^2 = 0.24, I^2 = 0%; 2 studies, 1395 participants; low-certainty evidence; Analysis 1.4). We downgraded the certainty of evidence to low due to very serious imprecision.
Subgroup analyses by type of immune checkpoint inhibitors (Analysis 2.4) did not reveal any subgroup effect.
Any adverse events
Amongst the five trials that reported adverse events (GeparNuevo; IMpassion031; KEYNOTE-522; NCI 10013; NeoTRIP), four trials utilised NCI-CTCAE version 4.0 to collect and categorise the adverse events (GeparNuevo; IMpassion031; KEYNOTE-522; NeoTRIP). The main adverse events observed in the PD-1 or PD-L1 inhibitors plus NACT arms included anaemia, neutropenia, fatigue, alopecia, nausea, diarrhoea, vomiting, peripheral sensory neuropathy, and abnormal liver transaminases.
Three trials with 1781 participants addressed any adverse events (IMpassion031; KEYNOTE-522; NeoTRIP). There is probably little or no difference between PD-1 or PD-L1 inhibitors plus NACT and NACT in any adverse events (OR 0.26, 95% CI 0.05 to 1.24; Chi^2 = 0.18, I^2 = 0%; 3 studies, 1781 participants; moderate-certainty evidence; Analysis 1.5). We downgraded the certainty of evidence to moderate because the 95% CI crossed the line of no effect.
Subgroup analysis by type of immune checkpoint inhibitors (Analysis 2.5) did not reveal a subgroup effect.
Serious adverse events
Five trials with 2016 participants reported SAEs (GeparNuevo; IMpassion031; KEYNOTE-522; NCI 10013; NeoTRIP). PD-1 or PD-L1 inhibitors plus NACT probably increase SAEs (OR 1.75, 95% CI 1.15 to 2.67; 5 studies, 2016 participants; moderate-certainty evidence; Analysis 1.6) compared with NACT. We downgraded the certainty of evidence to moderate due to substantial heterogeneity (Chi^2 = 9.75, I^2 = 59%).
Subgroup analysis by type of immune checkpoint inhibitors (Analysis 2.6) did not reveal a subgroup effect. Sensitivity analysis excluding a study with high risk of bias showed a similar result (OR 1.86, 95% CI 1.20 to 2.90; Chi^2 = 8.39, I^2 =64%; Analysis 6.1) to the primary analysis.
Treatment-related deaths

Figure 3. Forest plot showing the results of Analysis 1.7 to four decimal places.

PD-1/PD-L1 inhibitors plus NACT

NACT
Events Total

Weight

Risk Difference
IV, Random, 95% CI

Risk Difference
IV, Random, 95% CI

Study or Subgroup	Events | Total | | | |
I-SPY2 | 0 | 69 | 0 | 181 | 8.2% | 0.0000 [-0.0211 , 0.0211] | |
KEYNOTE-522 | 4 | 783 | 1 | 389 | 72.6% | 0.0025 [-0.0046 , 0.0096] | |
NCI 10013 | 0 | 45 | 0 | 16 | 0.5% | 0.0000 [-0.0857 , 0.0857] | |
NeoTRIP | 0 | 138 | 0 | 140 | 18.7% | 0.0000 [-0.0140 , 0.0140] | |

Total (Walda)
Total events:

4

1035

1

726

100.0%

0.0018 [-0.0042 , 0.0079]

Test for overall effect: Z = 0.60 (P = 0.55) | | | | | | -100	-50 Favours PD-1/PD-L1 inhibitors plus NACT | 50	100 Favours NACT

Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.13, df = 3 (P = 0.99); I² = 0%

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.

Four trials with 1761 participants reported treatment-related deaths (I-SPY2; KEYNOTE-522; NCI 10013; NeoTRIP). There was probably little or no difference between PD-1 or PD-L1 inhibitors plus NACT and NACT in treatment-related deaths (RD 0.2%, 95% CI -0.4% to 0.8%; 4 studies, 1761 participants; moderatecertainty evidence; Analysis 1.7; Figure 3) compared with NACT. We downgraded the certainty of evidence to moderate because the 95% CI crossed the line of no effect.
Subgroup analysis by type of immune checkpoint inhibitors (Analysis 2.7) did not reveal a subgroup effect.
PD-1 or PD-L1 inhibitors plus ACT versus ACT
See Summary of findings 2.
Primary outcome
Event-free survival
One trial with 2199 participants reported EFS (ALEXANDRA/ IMpassion030). There may be little or no difference between PD-1 or PD-L1 inhibitors plus ACT and ACT in EFS (HR 1.11, 95% CI 0.87 to 1.42; 1 study, 2199 participants; low-certainty evidence; Analysis 8.1). We downgraded the certainty of evidence to low due to high risk of bias and serious imprecision.
Secondary outcomes
Overall survival
One trial with 2199 participants reported OS (ALEXANDRA/ IMpassion030). There may be little or no difference between PD-1 or PD-L1 inhibitors plus ACT and ACT in OS (HR 1.23, 95% CI 0.87 to 1.73; 1 study, 2199 participants; low-certainty evidence; Analysis 8.2). We downgraded the certainty of evidence to low due to high risk of bias and serious imprecision.
Health-related quality of life
One trial with 2168 participants provided data on HRQoL from baseline to 24 months (ALEXANDRA/IMpassion030). There may be little or no difference between PD-1 or PD-L1 inhibitors plus ACT and ACT in HRQoL (MD -1.02, 95% CI -2.71 to 0.67; 1 study, 2168 participants; low-certainty evidence; Analysis 8.3). We downgraded the certainty of evidence to low due to high risk of bias and serious imprecision.
Any adverse events
One trial with 2177 participants addressed any adverse events (ALEXANDRA/IMpassion030). There may be little or no difference between PD-1 or PD-L1 inhibitors plus ACT and ACT in any adverse events (OR 3.38, 95% CI 0.93 to 12.33; 1 study, 2177 participants; low-certainty evidence; Analysis 8.4). We downgraded the certainty of evidence to low due to high risk of bias and serious imprecision.
Serious adverse events
One trial with 2177 participants reported SAEs (ALEXANDRA/ IMpassion030). PD-1 or PD-L1 inhibitors plus ACT probably increase SAEs compared with ACT (OR 1.81, 95% CI 1.47 to 2.24; 1 study, 2177 participants; moderate-certainty evidence; Analysis 8.5). We downgraded the certainty of evidence to moderate due to high risk of bias.
Treatment-related deaths
One trial with 2177 participants reported treatment-related deaths (ALEXANDRA/IMpassion030). There may be little or no difference between PD-1 or PD-L1 inhibitors plus ACT and ACT in treatment- related deaths (RD -0.1%, 95% CI -0.4% to 0.2%; 1 study, 2177 participants; low-certainty evidence; Analysis 8.6; Figure 4). We downgraded the certainty of evidence to low due to high risk of bias and serious imprecision.

Figure 4. Forest plot showing the results of Analysis 8.6 to four decimal places.
PD-1/PD-L1 inhibitors plus ACT	ACT	Risk Difference	Risk Difference
Study or Subgroup	Events	Total Events Total Weight IV, Random, 95% CI	IV, Random, 95% CI
ALEXANDRA/IMpassion030 | 0 | 1093 | 1 | 1084 | 100.0% | -0.0009 [-0.0035 , 0.0016] |
Total Total events: Test for overall effect: Z = 0.71 (P = 0.48) | 0 | 1093 | 1 | 1084 | 100.0% | -0.0009 [-0.0035 , 0.0016] -100 | -50 | | | 50 | 100
Favours PD-1/PD-L1 inhibitors plus ACT Favours ACT
Heterogeneity: Not applicable

D I S C U S S I O N
Summary of main results
This review provides sufficient evidence that PD-1 or PD-L1 inhibitors combined with chemotherapy before breast cancer surgery improve EFS, pathological complete response rate, and OS compared with chemotherapy alone. There may be little or no difference between PD-1 or PD-L1 inhibitors combined with chemotherapy and chemotherapy alone in HRQoL. Similarly, there did not appear to be a difference in any adverse events or treatment-related deaths. However, there was an increase in immune-related SAEs with PD-1 or PD-L1 inhibitors combined with chemotherapy compared to chemotherapy alone. These included hypothyroidism, hyperthyroidism, adrenal insufficiency, pneumonitis, thyroiditis, and hypophysitis.
Based on a single study, there may be little or no difference between PD-1 or PD-L1 inhibitors plus chemotherapy after surgery compared with chemotherapy alone in EFS, OS, HRQoL, any adverse events, and treatment-related deaths. However, immunotherapy combined with chemotherapy was associated with an increase in immune-related SAEs compared to chemotherapy alone.
Overall completeness and applicability of evidence
During the review process, we conducted comprehensive searches across multiple databases and selected relevant studies using strict inclusion criteria. However, we acknowledge that high-quality RCTs in this area are limited, which may have impacted the completeness of our evidence evaluation. Additionally, some eligible studies had certain methodological limitations such as small sample sizes, short follow-up durations, and lack of blinding, which may affect the reliability of the results.
Some meta-analyses showed substantial heterogeneity, which may affect the generalisability and applicability of the results. Although 
we performed subgroup analyses to explore potential sources of heterogeneity, limited data in certain subgroups reduced the precision and reliability of these analyses.
We focused on individuals with early TNBC, therefore the findings may not be generalisable to other subtypes or stages of breast cancer. Furthermore, the combination therapy of PD-1 or PD-L1 inhibitors with neoadjuvant chemotherapy may require specific techniques and resources for implementation, resulting in possible differences in its application in different regions or healthcare settings.
Quality of the evidence
PD-1 or PD-L1 inhibitors plus chemotherapy versus chemotherapy alone before breast cancer surgery
The certainty of evidence for this comparison ranged from low to high, downgraded due to serious inconsistency or serious imprecision (Summary of findings 1). We downgraded the certainty of evidence for pathological complete response by one level to moderate for inconsistency due to substantial heterogeneity. The certainty of evidence for EFS was not downgraded in any domain and was assessed as high. We downgraded the certainty of evidence for OS by one level to moderate due to substantial heterogeneity. We downgraded the certainty of evidence for HRQoL by two levels to low due to the 95% CI of the effect estimate crossing the null effect and the wide CI. We downgraded the certainty of evidence for any adverse events and treatment-related deaths by one level to moderate for imprecision due to the 95% CI crossing the null effect. We downgraded the certainty of evidence for SAEs by one level to moderate due to substantial heterogeneity.
PD-1 or PD-L1 inhibitors plus chemotherapy versus chemotherapy alone after breast cancer surgery
The certainty of evidence was low for most outcomes in this comparison, downgraded due to high risk of bias and serious imprecision (Summary of findings 2). For EFS, OS, any adverse events, and treatment-related deaths, we downgraded the certainty of evidence by one level for risk of bias due to early trial termination and one level for imprecision due to the 95% CI crossing the null effect, resulting in low-certainty evidence. We downgraded the certainty of evidence for HRQoL by one level for risk of bias due to lack of blinding and early trial termination and one level for imprecision due to the 95% CI crossing the null effect, resulting in low-certainty evidence. We downgraded the certainty of evidence for SAEs by one level to moderate for risk of bias due to early trial termination. As future trials become available for analysis, we anticipate that the certainty rating will improve for some outcomes.
Potential biases in the review process
The strengths of this review include a comprehensive search; duplicate study identification, data extraction, and assessment of the risk of bias; assessment of the certainty of evidence using the latest GRADE approach; and presentation of absolute effects for outcomes. Moreover, we conducted some prespecified subgroup analyses to explore the possible subgroup effect.
Although we performed comprehensive literature searches and included all eligible studies, only three trials provided data on HRQoL. Similarly, the data to address prespecified subgroup analyses, including PD-L1 status, age, and ECOG, were very limited. Consequently, the results for some outcomes and some subgroup analyses may lack statistical power. Furthermore, the method of PD-L1 status assessment and the cutoff points used to determine PD-L1 positivity could affect the results of PD-L1 status subgroup analyses. As the duration of interventions was similar across eligible trials, we did not perform subgroup analyses for the duration of intervention.
Given the inclusion of only seven trials, the assessment of publication bias using the funnel plot was not applicable. However, we conducted a comparison between the eligible trials and their corresponding protocols to evaluate outcome reporting bias and found no evidence of selective outcome reporting.
The NCI 10013 trial had a shorter median follow-up time compared to other studies, which may have influenced the results for pathological complete response rate and SAEs. Regarding the outcome of EFS, one trial (I-SPY2) did not report the 95% CI of the HR, and we extracted data from the Kaplan-Meier curve. Reassuringly, our sensitivity analysis excluding this trial yielded a similar result to the primary analysis of all trials. Although OS is generally expected to follow the results for EFS, and pathological complete response improved in the intervention group, the small average follow-up time is an important bottleneck to that conclusion. It is therefore expected that with longer followups or future assessments of those same cohorts, a change or confirmation of these results might occur.
Due to the open-label design, some of the included trials were at high or unclear risk of bias for lack of blinding of participants and personnel (performance bias) and outcome assessment (detection bias). Future trials should address these issues to enhance the methodological quality and minimise potential biases. Implementing blinding techniques, such as double-blinding, can help mitigate the impact of detection bias.
Agreements and disagreements with other studies or reviews
To our knowledge, six prior systematic reviews and meta-analyses have examined the effects of the combination of PD-1 or PD- L1 inhibitors and chemotherapy for the treatment of early TNBC (Mittal 2022; Qi 2022; Sternschuss 2021; Tarantino 2021; Xin 2021; Zhang 2022). These reviews reported that, compared to chemotherapy alone, the combination of PD-1 or PD-L1 inhibitors with chemotherapy may be associated with a significant improvement in the pathological complete response rate and EFS, whilst possibly also leading to an increased incidence of SAEs. However, these reviews have some limitations. Some reviews failed to include recently published trials (Mittal 2022; Qi 2022; Sternschuss 2021; Tarantino 2021; Zhang 2022); some overlooked the outcome of EFS (Qi 2022) or OS (Mittal 2022; Qi 2022; Sternschuss 2021; Tarantino 2021; Xin 2021); and some did not assess the certainty of the evidence (Qi 2022; Sternschuss 2021; Tarantino 2021; Zhang 2022). Additionally, none of them focused on the patient-important outcome of HRQoL.
Compared with previous meta-analyses (Mittal 2022; Qi 2022; Sternschuss 2021; Tarantino 2021; Xin 2021; Zhang 2022), our review assessed the certainty of evidence using the latest GRADE approach, evaluated more outcomes, presented absolute effects for outcomes, and tested more subgroup hypotheses. Consistent with previous meta-analyses, our review found that the addition of PD-1 or PD-L1 inhibitors to neoadjuvant chemotherapy relative to neoadjuvant chemotherapy alone is associated with an improvement in pathological complete response rate, EFS, and OS. However, the addition of PD-1 or PD-L1 inhibitors to chemotherapy compared to chemotherapy alone when given before breast cancer surgery is associated with immune-related SAEs.
A U T H O R S ' C O N C L U S I O N S
Implications for practice
Our review demonstrates that the addition of PD-1 or PD-L1 inhibitors to chemotherapy before surgery improves event-free survival, and probably improves pathological complete response and overall survival compared to chemotherapy alone. There is probably little or no difference in any adverse events and treatment-related deaths between PD-1 or PD-L1 inhibitors plus chemotherapy and chemotherapy alone when given prior to breast cancer surgery.
Based on a single study, there was no indication of improved outcomes when PD-1 or PD-L1 inhibitors were combined with chemotherapy compared to chemotherapy alone when treatment was given after breast cancer surgery.
Our review suggests that the addition of PD-1 or PD-L1 inhibitors to chemotherapy before or after surgery probably increases the risk of serious adverse events. Although our data on serious adverse events were limited, other data on the toxicity of these drugs can be gleaned from trials in other oncologic indications (e.g. Wang 2019; Zhou 2021). It is therefore important for healthcare professionals to carefully monitor for serious adverse events when administering PD-1 or PD-L1 inhibitors plus chemotherapy in early triple-negative breast cancer patients.
Implications for research
This review included seven randomised controlled trials with a total of 4341 participants, and the certainty of evidence ranged from low to high. To provide more robust and reliable evidence, future research should prioritise conducting well- designed randomised controlled trials with larger sample sizes and rigorous methodology.
The available evidence suggests that PD-1 or PD-L1 inhibitors plus chemotherapy in the neoadjuvant or adjuvant setting increases serious adverse events compared to chemotherapy alone. However, due to the limited sample size, future research should carefully monitor and report on adverse events, particularly serious adverse events, to provide a more comprehensive understanding of the safety profile associated with PD-1 or PD-L1 inhibitors plus chemotherapy.
Most included studies provided data on event-free survival and overall survival at a median follow-up ranging from 19.8 months to 43.7 months. It is essential to assess the longer-term effects of PD-1 or PD-L1 inhibitors plus chemotherapy on event-free survival and overall survival.
Future trials may also focus on the assessment of patient-important outcomes, such as health-related quality of life. Furthermore, it is important to explore clinically important subgroup effects, such as PD-L1 status, age, and Eastern Cooperative Oncology Group (ECOG) performance status, to enhance the understanding of the effects of interventions in specific patient populations.
A C K N O W L E D G E M E N T S
We would like to thank Melina Willson (Cochrane Breast Cancer Group) for the support in the development of this review. We would like to thank Peta Skeers for developing the search strategies.
Editorial and peer-reviewer contributions
Cochrane Breast Cancer Group supported the authors in the development of this review.
The following people conducted the editorial process for this article:
•		Sign-off Editor (final editorial decision): Toby Lasserson, Acting Editor in Chief, Cochrane;
•		Managing Editor (selected peer reviewers, provided editorial guidance to authors, edited the article): Samuel Hinsley, Cochrane Central Editorial Service;
•		Editorial Assistant (conducted editorial policy checks, collated peer-reviewer comments, and supported the editorial team): Addie-Ann Smyth, Cochrane Central Editorial Service;
•		Copy Editor (copy editing and production): Lisa Winer, Cochrane Central Production Service;
•		Peer reviewers (provided comments and recommended an editorial decision): Dario Trapani, European Institute of Oncology, IRCCS, Milan, Italy (clinical/content review), Edozie Iweka, University Hospitals of Derby and Burton NHS Foundation Trust, Derby, United Kingdom (clinical/ content review), Tiago Siqueira, Department of General Surgery – Hospital Israelita Albert Einstein, São Paulo, Brazil (clinical/content review), Nuala Livingstone, Cochrane Evidence Production and Methods Directorate (methods review), Yuan Chi, Beijing Yealth Technology Co, Ltd; McMaster University (search review).
REFERENCES

References to studies included in this review
ALEXANDRA/IMpassion030 {published and unpublished data}
Ignatiadis M, Bailey A, McArthur H, El-Abed S, de Azambuja E, Metzger O, et al. Adjuvant Atezolizumab for Early TripleNegative Breast Cancer: The ALEXANDRA/IMpassion030 Randomized Clinical Trial. JAMA 2025;333(13):1150-1160.
NCT03498716. A Study Comparing Atezolizumab (Anti PD- L1 Antibody) In Combination With Adjuvant Anthracycline/ Taxane-Based Chemotherapy Versus Chemotherapy Alone In Patients With Operable Triple-Negative Breast Cancer. https:// clinicaltrials.gov/study/NCT03498716 (first received 17 April 2018).
GeparNuevo {published data only}
Loibl S, Schneeweiss A, Huober J, Braun M, Rey J, Blohmer JU, et al. Neoadjuvant durvalumab improves survival in early triplenegative breast cancer independent of pathological complete response. Annals of Oncology 2022;33(11):1149-58.
Loibl S, Untch M, Burchardi N, Huober J, Sinn BV, Blohmer JU, et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Annals of Oncology 2019;30(8):1279-88.
IMpassion031 {published data only}
Barrios CH, Saji S, Harbeck N, Zhang H, Jung KH, Patel S, et al. Patient-reported outcomes from a randomized trial of neoadjuvant atezolizumab-chemotherapy in early triplenegative breast cancer. NPJ Breast Cancer 2022;8(1):108.
Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triplenegative breast cancer (IMpassion031): a randomised, doubleblind, phase 3 trial. Lancet 2020;396(10257):1090-100.
Saji S, Ohsumi S, Ito M, Hayashi N, Kobayashi K, Masuda N, et al. Subgroup analysis of Japanese patients in a phase III randomized, controlled study of neoadjuvant atezolizumab or placebo, combined with nab-paclitaxel and anthracycline- based chemotherapy in early triple-negative breast cancer (IMpassion031). Japanese Journal of Clinical Oncology 2022;52(10):1124-33.
I-SPY2 {published data only}
Nanda R, Liu MC, Yau C, Shatsky R, Pusztai L, Wallace A, et al. Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial. JAMA Oncology 2020;6(5):676-84.
KEYNOTE-522 {published data only}
Dent R, Cortés J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Neoadjuvant pembrolizumab plus chemotherapy/adjuvant pembrolizumab for early-stage triple-negative breast cancer: quality-of-life results from the randomized KEYNOTE-522 study. Journal of the National Cancer Institute 2024;116(10):1654-63.
Schmid P, Cortes J, Dent R, McArthur H, Pusztai L, Kümmel S, et al. Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer. New England Journal of Medicine 2024;391(121):1981-91.
Schmid P, Cortes J, Dent R, Pusztai L, McArthur H, Kümmel S, et al. Event-free Survival with Pembrolizumab in Early TripleNegative Breast Cancer. New England Journal of Medicine 2022;386(6):556-67.
Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. New England Journal of Medicine 2020;382(9):810-21.
Schmid P, Cortes L, Pusztai L, KEYNOTE-522 Investigators. Pembrolizumab plus Neoadjuvant Chemotherapy Improves Pathologic Complete Response Rates in Triple-Negative Breast Cancer. Journal of Clinical Outcomes Management 2020;27(2):53-5.
Takahashi M, Cortés J, Dent R, Pusztai L, McArthur H, Kümmel S, et al. Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Patients With Early Triple-Negative Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Network Open 2023;6(11):e2342107.
NCI 10013 {published data only}
Ademuyiwa FO, Gao F, Street CR, Chen I, Northfelt DW, Wesolowski R, et al. A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel with or without atezolizumab in triple negative breast cancer (TNBC) - NCI 10013. NPJ Breast Cancer 2022;8(1):134.
NCT02883062. Carboplatin and Paclitaxel With or Without Atezolizumab Before Surgery in Treating Patients With Newly Diagnosed, Stage II-III Triple-Negative Breast Cancer. https:// clinicaltrials.gov/study/NCT02883062 (first received 30 August 2016).
NeoTRIP {published data only}
Gianni L, Huang CS, Egle D, Bermejo B, Zamagni C, Thill M, et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high- risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study. Annals of Oncology 2022;33(5):534-43.
References to studies excluded from this review
ACTRN12617000651381 {unpublished data only}
ACTRN12617000651381. BCT 1702 (CHARIOT): Patients with high-risk primary triple negative breast cancer who have had anthracycline-based chemotherapy will receive Ipilimumab and Nivolumab with weekly paclitaxel, followed by definitive surgery and further treatment with Nivolumab to evaluate the safety, feasibility and efficacy of this treatment. https:// trialsearch.who.int/Trial2.aspx?TrialID=ACTRN12617000651381 (first received 5 May 2017).
ACTRN12619001308189 {unpublished data only}
ACTRN12619001308189. In patients with previously untreated early stage triple negative breast cancer, how well does using Nivolumab before starting standard chemotherapy, OR starting treatment with Nivolumab and chemotherapy at the same time, help to reduce tumour size before surgery compared. https:// trialsearch.who.int/Trial2.aspx?TrialID=ACTRN12619001308189 (first received 25 September 2019).
ChiCTR2100041675 {unpublished data only}
ChiCTR2100041675. Multicenter Clinical Study of Tislelizumab Combined with Nab-Paclitaxel and Carboplatin in
Neoadjuvant Therapy Followed by Adjuvant Therapy with Tislelizumab in Triple Negative Breast Cancer (TNBC). https:// www.chictr.org.cn/showproj.html?proj=66604 (first received 1 January 2021).
EUCTR2018-001155-13 {unpublished data only}
EUCTR2018-001155-13. Chemotherapy with or without Durvalumab in early-stage triple-negative breast cancer. https:// www.clinicaltrialsregister.eu/ctr-search/trial/2018-001155-13/ DE (first received 10 December 2018).
Fehrenbacher 2020 {published data only}
Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, et al. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. Journal of Clinical Oncology 2020;38(5):444-53.
Foldi 2022 {published data only}
Foldi J, Kahn A, Silber A, Qing T, Reisenbichler E, Fischbach N, et al. Clinical Outcomes and Immune Markers by Race in a Phase I/II Clinical Trial of Durvalumab Concomitant with Neoadjuvant Chemotherapy in Early-Stage TNBC. Clinical Cancer Research 2022;28(17):3720-8.
Khoury 2019 {published data only}
Khoury K, Isaacs C, Gatti-Mays ME, Donahue RN, Schlom J, Wang H, et al. Nivolumab or capecitabine or combination therapy as adjuvant therapy for triple negative breast cancer (TNBC) with residual disease following neoadjuvant chemotherapy: The OXEL study. Cancer Research 2019;79(4_Supplement):OT3-04-01.
NCT02322814 {published data only}
NCT02322814. A Study of Cobimetinib Plus Paclitaxel, Cobimetinib Plus Atezolizumab Plus Paclitaxel, or Cobimetinib Plus Atezolizumab Plus Nab-Paclitaxel as Initial Treatment for Participants With Triple-Negative Breast Cancer That Has Spread. https://clinicaltrials.gov/study/NCT02322814 (first received 23 December 2014).
NCT02530489 {unpublished data only}
NCT02530489. Nab-Paclitaxel and Atezolizumab Before Surgery in Treating Patients With Triple Negative Breast Cancer. https:// clinicaltrials.gov/study/NCT02530489 (first received 21 August 2015).
NCT02622074 {published data only}
NCT02622074. Safety and Efficacy Study of Pembrolizumab (MK-3475) in Combination With Chemotherapy as Neoadjuvant Treatment for Participants With Triple Negative Breast Cancer (TNBC) (MK-3475-173/KEYNOTE-173). https://clinicaltrials.gov/ study/NCT02622074 (first received 4 December 2015).
NCT02685059 {unpublished data only}
NCT02685059. Addition of PD-L1 Antibody MEDI4736 to a Taxane-anthracycline Chemotherapy in Triple Negative Breast Cancer. https://clinicaltrials.gov/study/NCT02685059 (first received 18 February 2016).
NCT03036488 {unpublished data only}
NCT03036488. Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy in Participants With Triple Negative Breast Cancer (TNBC) (MK-3475-522/KEYNOTE-522). https://clinicaltrials.gov/study/ NCT03036488 (first received 30 January 2017).
NCT03251313 {unpublished data only}
NCT03251313. PD-1 (Programmed Death-1) Antibody +GP as First Line Treatment for Triple Negative Breast Cancer(TNBC) Patients. https://clinicaltrials.gov/study/NCT03251313 (first received 16 August 2017).
NCT03281954 {unpublished data only}
NCT03281954. Clinical Trial of Neoadjuvant Chemotherapy With Atezolizumab or Placebo in Patients With Triple-Negative Breast Cancer Followed After Surgery by Atezolizumab or Placebo. https://clinicaltrials.gov/study/NCT03281954 (first received 13 September 2017).
NCT03487666 {unpublished data only}
NCT03487666. OXEL: Immune Checkpoint or Capecitabine or Combination Therapy as Adjuvant Therapy for TNBC With Residual Disease. https://clinicaltrials.gov/study/NCT03487666 (first received 4 April 2018).
NCT03639948 {unpublished data only}
NCT03639948. Neoadjuvant Phase II Study of Pembrolizumab and Carboplatin Plus Docetaxel in Triple Negative Breast Cancer. https://clinicaltrials.gov/study/NCT03639948 (first received 21 August 2018).
NCT03719326 {unpublished data only}
NCT03719326. A Study to Evaluate Safety/Tolerability of Immunotherapy Combinations in Participants With TripleNegative Breast Cancer or Gynecologic Malignancies. https:// clinicaltrials.gov/study/NCT03719326 (first received 25 October 2018).
NCT03756298 {unpublished data only}
NCT03756298. Efficacy and Safety of Atezolizumab Plus Capecitabine Adjuvant Therapy for Triple Receptor-Negative Breast Cancer. https://clinicaltrials.gov/study/NCT03756298 (first received 28 November 2018).
NCT04191135 {unpublished data only}
NCT04191135. Study of Olaparib Plus Pembrolizumab Versus Chemotherapy Plus Pembrolizumab After Induction With First- Line Chemotherapy Plus Pembrolizumab in Triple Negative Breast Cancer (TNBC) (MK-7339-009/KEYLYNK-009). https:// clinicaltrials.gov/study/NCT04191135 (first received 9 December 2019).
NCT04331067 {unpublished data only}
NCT04331067. Neoadjuvant Nivolumab and Chemotherapy in Patients With Localized Triple-negative Breast Cancer. https:// clinicaltrials.gov/study/NCT04331067 (first received 2 April 2020).
NCT04809779 {unpublished data only}
NCT04809779. PD-1 Inhibitor Concurrent With Chemotherapy as Neoadjuvant Therapy for TNBC. https://clinicaltrials.gov/study/ NCT04809779 (first received 22 March 2021).
NCT05088057 {unpublished data only}
NCT05088057. A Phase Ⅱ Study to Evaluate the Efficacy and Safety of Camrelizumab Plus Chemotherapy as Neoadjuvant Therapy With Triple Negative Breast Cancer (TNBC). https:// clinicaltrials.gov/study/NCT05088057 (first received 21 October 2021).
NCT05215106 {unpublished data only}
NCT05215106. Short-term Pre-OPerative Durvalumab (MEDI 4736) in Early Small Triple Negative Breast Cancer Patients (POP-Durva). https://clinicaltrials.gov/study/NCT05215106 (first received 31 January 2022).
NCT05556200 {unpublished data only}
NCT05556200. A Phase II Trial of Camrelizumab in Combination With Apatinib for Neoadjuvant Treatment of Early-stage TNBC With a High Proportion of TILs. https://clinicaltrials.gov/study/ NCT05556200 (first received 27 September 2022).
NCT05681728 {unpublished data only}
NCT05681728. A Phase II Study Evaluating the Efficacy and Safety of Pembrolizumab in Combination With Chemotherapy as Neoadjuvant Therapy for Triple-negative Breast Cancer. https://clinicaltrials.gov/study/NCT05681728 (first received 12 January 2023).
NCT05877859 {unpublished data only}
NCT05877859. Evaluating and Monitoring Immune and Clinical Responses in Early-Stage Triple Negative Breast Cancer Undergoing Neoadjuvant Chemo-immunotherapy With Pembrolizumab. https://clinicaltrials.gov/study/NCT05877859 (first received 26 May 2023).
NCT06604858 {unpublished data only}
NCT06604858. Neoadjuvant Phase II Study of Pembrolizumab and Carboplatin Plus Paclitaxel for Stage I Triple-negative Breast Cancer (The TELESCOPE Study). https://clinicaltrials.gov/study/ NCT06604858 (first received 20 September 2024).
Pusztai 2024 {published data only}
Pusztai L, Denkert C, O'Shaughnessy J, Cortes J, Dent R, McArthur H, et al. Event-free survival by residual cancer burden
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References to studies awaiting assessment
NCT03356860 {unpublished data only}
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NCT04301739 {unpublished data only}
NCT04301739. A Randomized, Double-Blind, International Multi-Centre, Phase III Clinical Study to Evaluate Efficacy and Safety of HLX10 in Combination With Chemotherapy Versus Placebo in Combination With Chemotherapy as Neoadjuvant Therapy and HLX10 Versus Placebo as Adjuvant Therapy in Patients With Triple Negative Breast Cancer (TNBC). https:// clinicaltrials.gov/study/NCT04301739 (first received 10 March 2020).
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C H A R A C T E R I S T I C S O F S T U D I E S
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ALEXANDRA/IMpassion030
Study characteristics

Methods

Accrual time: August 2018 to August 2023
Phase III RCT, open label
Multicentre
Countries: Argentina, Australia, Austria, Belgium, Brazil, China, Czechia, Denmark, France, Germany, Hungary, Ireland, Israel, Italy, Japan, Republic of Korea, Mexico, Peru, Poland, Romania, Russian Federation, Singapore, Spain, Switzerland, Thailand, Turkey, Ukraine, UK, USA
Median follow-up: 32.3 months in the atezolizumab plus chemotherapy group; 31.9 months in the chemotherapy group

Participants

Sample size: 2199
Median age: 53 years in atezolizumab plus chemotherapy group; 53 years in chemotherapy group

ALEXANDRA/IMpassion030 (Continued)

Inclusion criteria: eligible patients were aged 18 years or older with non-metastatic operable stage II or III TNBC (no ERBB2 amplification
or HER2 overexpression, <1% expression of oestrogen and progesterone receptors, determined at a central laboratory according to the American Society of Clinical Oncology/College of American Pathologists) that had been adequately excised (breast-conserving surgery or mastectomy). Sentinel lymph node biopsy and/or axillary lymph node dissection was mandatory to evaluate pathological nodal status. It was planned to enrol a population enriched (≥50%) for node-positive disease; patients with node-negative disease had to have a pathological tumour size of 2 cm or larger. A representative formalin-fixed paraffin-embedded tumour specimen was required from all patients before enrolment for central evaluation of PD-L1 status using the VENTANA SP142 immunohistochemistry assay (Roche Diagnostics).
Exclusion criteria: patients with a history of invasive breast cancer; any T4 tumour; prior systemic anticancer treatment for the currently diagnosed breast cancer; or prior anthracycline, taxane, or immune checkpoint inhibitor therapy.

Interventions

Intervention arm: atezolizumab 840 mg every 2 weeks for up to 10 doses, followed by 1200 mg of maintenance atezolizumab every 3 weeks for up to 1 year in total plus paclitaxel 80 mg/m^2 every week for 12 weeks followed by 60 mg/m^2 of dose-dense doxorubicin or 90 mg/m^2 of dose-dense epirubicin (investigator’s choice) given with 600 mg/m^2 of cyclophosphamide every 2 weeks for 4 cycles, supported with granulocyte or granulocyte-macrophage colony-stimulating factor
Control arm: paclitaxel 80 mg/m^2 every week for 12 weeks followed by 60 mg/m^2 of dose-dense doxorubicin or 90 mg/m^2 of dose-dense epirubicin (investigator’s choice) given with 600 mg/m^2 of cyclophosphamide every 2 weeks for 4 cycles, supported with granulocyte or granulocyte-macrophage colony-stimulating factor

Outcomes

Primary outcome
Invasive disease-free survival: interval between randomisation and the first ipsilateral invasive breast tumour recurrence, ipsilateral local-regional invasive breast cancer recurrence, ipsilateral second primary invasive breast cancer, contralateral invasive breast cancer, distant recurrence, or death from any cause
Secondary outcomes
OS: time from randomisation to the date of death due to any cause
HRQoL: measured using the global health status (GHS)/QoL scale of the EORTC QLQ-30
Any adverse event: any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. Any adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events. Any adverse events are reported based on the NCI CTCAE, version 5.0.
SAEs: based on NCI CTCAE, version 5.0
Treatment-related deaths

Notes

Trials registration link: https://clinicaltrials.gov/study/NCT03498716
Funding support: Hoffmann-La Roche

Risk of bias
Bias | Authors' judgement Support for judgement

Random sequence generation (selection bias)

Low risk	Randomization used permuted blocks, with a fixed block size; the random al
locations were generated by an external interactive voice- or web-based re-

ALEXANDRA/IMpassion030 (Continued) | sponse system (iXRS) company, with participants enrolled at each site using the iXRS.

Allocation concealment	Low risk
(selection bias)

The study team was blinded to PD-L1 status and had restricted access to the randomization lists.

Blinding of participants	Low risk
and personnel (performance bias)
Event-free survival

Objective, blinding of participants and personnel is generally not a concern

Blinding of participants	Low risk
and personnel (performance bias)
Overall survival

Objective, blinding of participants and personnel is generally not a concern

Blinding of participants	High risk
and personnel (performance bias)
Health-related quality of
life

Open-label

Blinding of participants	Low risk
and personnel (performance bias)
Any adverse events

Safety assessments were categorized according to the NCI-CTCAE version 5.0. Blinding of participants and personnel is generally not a concern

Blinding of participants	Low risk
and personnel (performance bias)
Serious adverse events

Safety assessments were categorized according to the NCI-CTCAE version 5.0. Blinding of participants and personnel is generally not a concern

Blinding of participants	Low risk
and personnel (performance bias)
Treatment-related deaths

Objective outcome

Blinding of outcome as-	Low risk
sessment (detection bias)
Event-free survival

Objective outcome

Blinding of outcome as-	Low risk
sessment (detection bias)
Overall survival

Objective outcome

Blinding of outcome as-	High risk
sessment (detection bias)
Health-related quality of
life

Open-label

Blinding of outcome as-	Low risk
sessment (detection bias)
Any adverse events

Safety assessments were categorized according to the NCI-CTCAE version 5.0. Blinding of participants and personnel is generally not a concern

Blinding of outcome as-	Low risk
sessment (detection bias)
Serious adverse events

Safety assessments were categorized according
to the NCI-CTCAE version 5.0. Blinding of participants and personnel is generally not a concern

ALEXANDRA/IMpassion030 (Continued)

Blinding of outcome as-	Low risk
sessment (detection bias)
Treatment-related deaths

Objective outcome

Incomplete outcome data Low risk (attrition bias)
All outcomes

Missing data < 5%.

Selective reporting (re-	Low risk
porting bias)

All outcomes were pre-specified.

Other bias	Low risk | No other biase

GeparNuevo
Study characteristics

Methods

Accrual time: June 2016 to October 2017
Phase II RCT
Multicentre
Country: Germany
Median follow-up: 43.7 months

Participants

Sample size: 174
Median age: 49.5 years in durvalumab plus chemotherapy group; 49.5 years in chemotherapy group
Inclusion criteria: patients with previously untreated uni- or bilateral primary, non-metastatic invasive TNBC with a tumour of at least 2 cm (cT2-cT4a-d) were enrolled after providing written informed consent for study participation. Tissue from the core biopsy had to be centrally available for translational research and histological confirmation of the triple negativity, determination of sTILs, PD-L1 and Ki-67. The negativity for ER- was defined as <1% IHC stained cells, for PR as <10% stained cells, and for HER2 as either IHC 0/1 or IHC 2+ and in situ hybridisation of either ratio <2.0 or <6 copies of HER2 per tumour cell.
Exclusion criteria: abnormal thyroid function, abnormal cardiac function (left ventricular ejection fraction < 55%), evidence of autoimmune disease and conditions, active or prior inflammatory bowel disease, primary immunodeficiency, previous clinical diagnosis of tuberculosis, acute or chronic hepatitis B or C or of HIV, distant disease or known or suspected cardiac disease, pre-existing peripheral sensory neuropathy grade ≥ 2, incomplete wound healing or unhealed bone fracture, and concurrent treatment with other anticancer or investigational agents.

Interventions

Intervention arm: durvalumab 1.5 g every 4 weeks added to nab-paclitaxel 125 mg/m^2 weekly for 12 weeks, followed by durvalumab 1.5 g every 4 weeks plus epirubicin/cyclophosphamide every 2 weeks for 4 cycles
Control arm: placebo every 4 weeks added to nab-paclitaxel 125 mg/m^2 weekly for 12 weeks, followed by placebo every 4 weeks plus epirubicin/cyclophosphamide every 2 weeks for 4 cycles

Outcomes

Primary outcomes
Pathological complete response: no invasive and no non-invasive tumour residuals in breast and in axillary lymph nodes (ypT0 ypN0) after neoadjuvant therapy

GeparNuevo (Continued)

EFS: locoregional (ipsilateral breast, locoregional lymph nodes, contralateral) breast cancer recurrence, any distant recurrence, any secondary malignancy, or death due to any cause, whichever occurred first, time from randomisation to first event occurred
Secondary outcomes
OS: time from randomisation to death due to any cause
SAEs: toxicity reported as serious adverse events irrespective of relatedness to study treatment were based on NCI-CTC criteria v4.0

Notes

Trials registration link: https://clinicaltrials.gov/study/NCT02685059
All randomised participants were included in the intention-to-treat analysis.
Funding support: AstraZeneca Germany and Celgene Germany

Risk of bias

Bias | Authors' judgement Support for judgement

Random sequence generation (selection bias)

Low risk	The randomisation was carried out centrally at German Breast Group GBG
headquarters in a 1: 1 ratio using a computerised system.

Allocation concealment (selection bias) | Low risk	Central allocation

Blinding of participants and personnel (performance bias)
Pathological complete response

Low risk	Double-blind

Blinding of participants and personnel (performance bias)
Event-free survival

Low risk	Double-blind

Blinding of participants and personnel (performance bias)
Overall survival

Low risk	Double-blind

Blinding of participants and personnel (performance bias)
Serious adverse events

Low risk	Double-blind

Blinding of outcome assessment (detection bias) Pathological complete response

Low risk	All histopathological reports were also centrally collected and evaluated by an
independent, blinded pathologist.

Blinding of outcome assessment (detection bias) Event-free survival | Low risk	Objective outcome
Blinding of outcome assessment (detection bias) Overall survival | Low risk	Objective outcome

GeparNuevo (Continued)
Blinding of outcome assessment (detection bias) Serious adverse events | Low risk	Measured based on NCI-CTC criteria v4.0

Incomplete outcome data (attrition bias)
All outcomes

Low risk	Durvalumab or placebo was discontinued in 22.7% and 19.8%, respectively.
Reasons for discontinuation were similar in both treatment arms.

Selective reporting (reporting bias) | Low risk	All outcomes were pre-specified.
Other bias | Low risk	No other bias

IMpassion031
Study characteristics

Methods

Accrual time: July 2017 to September 2019
Phase III RCT
Multicentre
Countries: Australia, Belgium, Brazil, Canada, Germany, Italy, Japan, Poland, South Korea, Spain, China, UK, and USA
Median follow-up: 20.6 months in the atezolizumab plus chemotherapy group; 19.8 months in the placebo plus chemotherapy group

Participants

Sample size: 333
Median age: 51 years in atezolizumab plus chemotherapy group; 51 years in chemotherapy group
Inclusion criteria: women or men aged 18 years or older; had clinical stage cT2–T4 (tumour size of >2 cm by at least one radiographic or clinical measurement) and cN0–cN3 histologically documented TNBC (by central assessment of negative HER2, oestrogen receptor, and progesterone receptor status according to American Society of Clinical Oncology/College of American Pathologists guidelines); had received no previous systemic therapy for breast cancer and no previous systemic therapy with an- thracyclines or taxanes for any malignancy; had an Eastern Cooperative Oncology Group performance score of 0 or 1; and had confirmed centrally assessed evaluation of tumour PD-L1 status as measured by the VENTANA SP142 assay, with PD-L1 positive defined as PD-L1-expressing tumour infiltrating immune cells covering 1% or more of the tumour area. The PD-L1-positive population was defined as all patients in the all-randomised population who had PD-L1-positive tumours at randomisation.
Exclusion criteria: previous treatment with an anti-CTLA-4, anti-PD-1, or anti-PD-L1 agent for any malignancy; history of ductal or pleomorphic lobular carcinoma in situ unless more than 5 years before the current diagnosis and treated only surgically; bilateral breast cancer; or the patient had undergone incisional or excisional biopsy, or both, of primary tumour or axillary lymph nodes, or both, or axillary lymph node dissection before initiation of neoadjuvant therapy.

Interventions

Intervention arm: atezolizumab at 840 mg every 2 weeks, nab-paclitaxel at 125 mg/m^2 every week for 12 weeks followed by doxorubicin at 60 mg/m^2 and cyclophosphamide at 600 mg/m^2 every 2 weeks for 8 weeks
Control arm: nab-paclitaxel at 125 mg/m^2 every week for 12 weeks followed by doxorubicin at 60 mg/ m^2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks

Outcomes | Primary outcomes

IMpassion031 (Continued)

Pathological complete response: eradication of invasive tumour for both breast and lymph nodes
EFS: time from randomisation to disease recurrence, progression, or death because of any cause
Secondary outcomes
OS: time from randomisation to death due to any cause
HRQoL: measured using the global health status (GHS)/QoL scale of the EORTC QLQ-30
Any adverse events: based on NCI CTCAE, version 4.0, safety was assessed for all participants who received any dose of study medication, and summaries of adverse events are presented by actual treatment group
SAEs: based on NCI CTCAE, version 4.0

Notes

Trials registration link: https://clinicaltrials.gov/study/NCT03197935
All randomised participants were included in the intention-to-treat analysis.
Funding support: F Hoffmann-La Roche/Genentech

Risk of bias

Bias | Authors' judgement Support for judgement

Random sequence generation (selection bias)

Low risk	Patients were randomly assigned (1:1) using a permuted block randomisation
method.

Allocation concealment (selection bias)

Low risk	The sponsor and investigators remained masked to treatment assignment and
PD-L1 status until the primary analysis of pathological complete response at the end of study stage 2.

Blinding of participants and personnel (performance bias)
Pathological complete response

Low risk	Treatment was unmasked to site personnel, including the investigator, after
assessment of pathological complete response to inform further treatment after surgery.

Blinding of participants and personnel (performance bias)
Event-free survival

Low risk	double-blind

Blinding of participants and personnel (performance bias)
Overall survival

Low risk	double-blind

Blinding of participants and personnel (performance bias)
Health-related quality of life

Low risk	double-blind

Blinding of participants and personnel (performance bias)
Any adverse events

Low risk	double-blind

IMpassion031 (Continued)

Blinding of participants and personnel (performance bias)
Serious adverse events

Low risk

double-blind

Blinding of outcome assessment (detection bias) Pathological complete response | Low risk | Treatment was unmasked to site personnel, including the investigator, after assessment of pathological complete response to inform further treatment after surgery.
Blinding of outcome assessment (detection bias) Event-free survival | Low risk | Objective outcome
Blinding of outcome assessment (detection bias) Overall survival | Low risk | Objective outcome
Blinding of outcome assessment (detection bias) Health-related quality of life | Unclear risk | No information
Blinding of outcome assessment (detection bias) Any adverse events | Low risk | An independent data monitoring committee reviewed unmasked safety and study conduct data every 6 months and at the first interim analysis to make a recommendation for study stage 2.
Blinding of outcome assessment (detection bias) Serious adverse events | Low risk | An independent data monitoring committee reviewed unmasked safety and study conduct data every 6 months and at the first interim analysis to make a recommendation for study stage 2.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

11 (6.67%) and 15 (8.935) patients had missing assessments in the atezolizum- ab plus chemotherapy group and placebo plus chemotherapy group, respectively.

Selective reporting (reporting bias) | Low risk | All outcomes were pre-specified.
Other bias | Low risk | No other bias

I-SPY2
Study characteristics

Methods

Accrual time: March 2010 to November 2016
Phase II adaptively RCT
Multicentre
Country: USA
Median follow-up: 2.8 years in the pembrolizumab plus chemotherapy group; 3.5 years in chemotherapy group

Participants | Sample size: 114

I-SPY2 (Continued)

Median age: 50 years in pembrolizumab plus chemotherapy group; 47 years in chemotherapy group
Inclusion criteria: patients eligible for I-SPY2 are women aged 18 years or older, with stage II or III breast cancer and primary tumours larger than 2.5 cm by clinical examination or larger than 2.0 cm by imaging, and Eastern Cooperative Oncology Group performance status of 0 or 1. Only ERBB2-negative patients were eligible for randomisation to the pembrolizumab arm.
Exclusion criteria: patients with MammaPrint low-risk HR positive, ERBB2-negative disease are excluded from I-SPY2 because their lower risk of recurrence does not justify escalation of therapy. All patients provide written informed consent prior to screening and again after randomisation.

Interventions

Intervention arm: 200 mg intravenous pembrolizumab every 3 weeks for 4 cycles (weeks 1, 4, 7, and 10) concurrently with paclitaxel plus 80 mg/m^2 intravenous paclitaxel weekly for 12 weeks, followed by 4 cycles of 60 mg/m^2 doxorubicin plus 600 mg/m^2 intravenous cyclophosphamide every 2 to 3 weeks
Control arm: 80 mg/m^2 intravenous paclitaxel weekly for 12 weeks, followed by 4 cycles of 60 mg/m^2 doxorubicin plus 600 mg/m^2 intravenous cyclophosphamide every 2 to 3 weeks

Outcomes

Primary outcomes
Pathological complete response: absence of invasive tumour in breast and regional nodes at the time of surgery
EFS: not reported
Secondary outcome
Treatment-related deaths

Notes

Trials registration link: https://clinicaltrials.gov/study/NCT01042379
108 of 114 randomised participants were included in the intention-to-treat analysis.
Funding support: Quantum Leap Healthcare Collaborative and the Foundation for the National Institutes of Health and the National Cancer Institute Center for Biomedical Informatics and Information Technology

Risk of bias

Bias | Authors' judgement Support for judgement
Random sequence generation (selection bias) | Low risk	Adaptive randomisation
Allocation concealment (selection bias) | Unclear risk	No information

Blinding of participants and personnel (performance bias)
Pathological complete response

Low risk	A study-trained pathologist evaluated pathological complete response. Blind
ing of participants and personnel is generally not a concern

Blinding of participants and personnel (performance bias)
Event-free survival

Low risk	Objective, blinding of participants and personnel is generally not a concern

Blinding of participants and personnel (performance bias) | Low risk	Objective outcome

I-SPY2 (Continued)
Treatment-related deaths

Blinding of outcome as-	Low risk
sessment (detection bias)
Pathological complete re
sponse

A study-trained pathologist evaluated pathological complete response. The Study Lead Pathologist made the final determination on any indeterminate or contested results.

Blinding of outcome as-	Low risk
sessment (detection bias)
Event-free survival

Objective outcome

Blinding of outcome as-	Low risk
sessment (detection bias)
Treatment-related deaths

Objective outcome

Incomplete outcome data Low risk (attrition bias)
All outcomes

Missing data < 7.41%.

Selective reporting (re-	Low risk
porting bias)

All outcomes were pre-specified.

Other bias	Low risk | No other bias

KEYNOTE-522
Study characteristics

Methods

Accrual time: March 2017 to September 2018
Phase III RCT
Multicentre
Countries: Australia, Brazil, Canada, Colombia, France, Germany, Ireland, Israel, Italy, Japan, Poland, Portugal, Russia, Singapore, South Korea, Spain, Sweden, China, Turkey, UK, USA
Median follow-up: 75.1 months

Participants

Sample size: 1174
Median age: 49 years in pembrolizumab plus chemotherapy group; 48 years in chemotherapy group
Inclusion criteria: patients were eligible for enrolment if they were at least 18 years of age and had centrally confirmed triple-negative breast cancer in all foci (as defined by the guidelines of the American Society of Clinical Oncology – College of American Pathologists); newly diagnosed, previously untreated, non-metastatic disease (tumour stage T1c, nodal stage N1-2, or tumour stage T2-4, nodal stage N0-2, according to the primary tumour – regional lymph node staging criteria of the American Joint Committee on Cancer, 7th edition), as determined by the investigator in radiologic assessment, clinical assessment, or both; an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a 5-point scale, with higher numbers indicating greater disability); and adequate organ function. Patients with bilateral or multifocal primary tumours and inflammatory breast cancers were eligible for enrolment.
Exclusion criteria: active autoimmune disease for which the patient had received systemic treatment within the previous 2 years, a diagnosis of immunodeficiency or use of immunosuppressive therapy within the previous week, a history of HIV infection, a history of non-infectious pneumonitis for which the patient had received glucocorticoids, current pneumonitis, active tuberculosis, active hepatitis B

KEYNOTE-522 (Continued) | virus or hepatitis C virus infection, any active infection for which the patient was receiving systemic therapy, and clinically significant cardiovascular disease.

Interventions

Intervention arm: an intravenous infusion of pembrolizumab (200 mg) once every 3 weeks plus paclitaxel (80 mg/m^2 once weekly) plus carboplatin (at a dose based on an area under the concentration – time curve of 5 mg/mL/min once every 3 weeks or 1.5 mg/mL/min once weekly in the first 12 weeks) (first neoadjuvant treatment), followed by 4 cycles of pembrolizumab plus doxorubicin (60 mg/m^2) or epirubicin (90 mg/m^2) plus cyclophosphamide (600 mg/m^2 once every 3 weeks in the subsequent 12 weeks) (second neoadjuvant treatment).
Control arm: paclitaxel (80 mg/m^2 once weekly) plus carboplatin (at a dose based on an area under the concentration – time curve of 5 mg/mL/min once every 3 weeks or 1.5 mg/mL/min once weekly in the first 12 weeks) (first neoadjuvant treatment), followed by doxorubicin (60 mg/m^2) or epirubicin (90 mg/m^2) plus cyclophosphamide (600 mg/m^2 once every 3 weeks in the subsequent 12 weeks) (second neoadjuvant treatment).

Outcomes

Primary outcomes
Pathological complete response: pathological stage ypT0/Tis ypN0 at the time of definitive surgery
EFS: time from randomisation to disease progression that precludes definitive surgery, local or distant recurrence, a second primary cancer, or death from any cause, whichever occurred first
Secondary outcomes
OS: time from randomisation to death due to any cause
HRQoL: measured using the global health status (GHS)/QoL scale of the EORTC QLQ-30
Any adverse events: defined as any untoward medical occurrence in a participant administered study treatment which does not necessarily have to have a causal relationship with this treatment
SAEs: based on NCI CTCAE, version 4.0
Treatment-related deaths

Notes

Trials registration link: https://clinicaltrials.gov/study/NCT03036488
All randomised participants were included in the intention-to-treat analysis.
Funding support: Merck Sharp & Dohme

Risk of bias

Bias | Authors' judgement Support for judgement

Random sequence generation (selection bias)

Low risk	Randomisation was performed with the use of a central interactive voice-re
sponse system with an integrated Web response system

Allocation concealment (selection bias) | Low risk	Central randomisation

Blinding of participants and personnel (performance bias)
Pathological complete response

Low risk	Double-blind

Blinding of participants and personnel (performance bias) | Low risk	Double-blind

KEYNOTE-522 (Continued)
Event-free survival

Blinding of participants	Low risk
and personnel (performance bias)
Overall survival

Double-blind

Blinding of participants	Low risk
and personnel (performance bias)
Health-related quality of
life

Double-blind

Blinding of participants	Low risk
and personnel (performance bias)
Any adverse events

Double-blind

Blinding of participants	Low risk
and personnel (performance bias)
Serious adverse events

Double-blind

Blinding of participants	Low risk
and personnel (performance bias)
Treatment-related deaths

Objective outcome

Blinding of outcome as-	Low risk
sessment (detection bias)
Pathological complete re
sponse

An external, independent data monitoring committee oversaw the trial, periodically assessed safety, and assessed efficacy at prespecified interim analyses

Blinding of outcome as-	Low risk
sessment (detection bias)
Event-free survival

An external, independent data monitoring committee oversaw the trial, periodically assessed safety, and assessed efficacy at prespecified interim analyses

Blinding of outcome as-	Low risk
sessment (detection bias)
Overall survival

An external, independent data monitoring committee oversaw the trial, periodically assessed safety, and assessed efficacy at prespecified interim analyses

Blinding of outcome as-	Unclear risk
sessment (detection bias)
Health-related quality of
life

No information

Blinding of outcome as-	Low risk
sessment (detection bias)
Any adverse events

An external, independent data monitoring committee oversaw the trial, periodically assessed safety, and assessed efficacy at prespecified interim analyses

Blinding of outcome as-	Low risk
sessment (detection bias)
Serious adverse events

An external, independent data monitoring committee oversaw the trial, periodically assessed safety, and assessed efficacy at prespecified interim analyses

Blinding of outcome as-	Low risk
sessment (detection bias)
Treatment-related deaths

Objective outcome

KEYNOTE-522 (Continued)

Incomplete outcome data Low risk (attrition bias)
All outcomes

Missing data is small

Selective reporting (re-	Low risk
porting bias)

All outcomes were pre-specified.

Other bias	Low risk | No other bias

NCI 10013
Study characteristics

Methods

Accrual time: August 2017 to September 2019
Phase II RCT
Multicentre
Country: USA
Median follow-up: 6.6 months

Participants

Sample size: 67
Median age: 49 years in atezolizumab plus chemotherapy group; 54 years in chemotherapy group
Inclusion criteria: eligible women had newly diagnosed, untreated triple negative breast cancer, defined as ER and PR < Allred score of 3 or ≤ 5% positive staining cells in the invasive component of the tumour. HER2 negative disease was defined as negative by FISH or IHC staining 0 or 1+ according to the American Society of Clinical Oncology and the College of American Pathologists guidelines. Patients had clinical stage T2-T4c, any N, M0 primary tumour by AJCC 7th edition clinical staging. Other key eligibility requirements were age ≥18 years, Eastern Cooperative Oncology Group performance status of ≤2, adequate organ function, and willingness and ability to provide informed consent.
Exclusion criteria: patients with contralateral breast cancer, a history of autoimmune disease, uncontrolled intercurrent illness, or treatment with immunosuppressive medications were excluded.

Interventions

Intervention arm: carboplatin AUC5 every 3 weeks X 4 cycles plus paclitaxel 80 mg/m^2 every week X 12 weeks plus atezolizumab 1200 mg every 3 weeks X 4 cycles
Control arm: carboplatin AUC5 every 3 weeks X 4 cycles plus paclitaxel 80 mg/m^2 every week X 12 weeks

Outcomes

Primary outcome
Pathological complete response: absence of residual invasive cancer in the surgical breast tissue and lymph node specimens
Secondary outcome
SAEs, defined as any death, life-threatening adverse event, inpatient or prolonged existing hospitalisation for ≥24 h, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect, or other experience which may jeopardize the participant and may require medical or surgical intervention to prevent one of the aforementioned outcomes.
Treatment-related deaths

NCI 10013 (Continued)

Notes

Trials registration link: https://clinicaltrials.gov/study/NCT02883062
61 of 67 randomised participants were included in the intention-to-treat analysis.
Funding support: National Cancer Institute, USA

Risk of bias | |
Bias | Authors' judgement | Support for judgement
Random sequence generation (selection bias) | Low risk | Randomisation was centralised using the Interactive Web Response System (IWRS).
Allocation concealment (selection bias) | Low risk | Central randomisation

Blinding of participants and personnel (performance bias)
Pathological complete response

Low risk

Two subspecialized breast pathologists independently reviewed whole slide scans (blinded to each other, treatment status, and time point). Blinding of participants and personnel is generally not a concern

Blinding of participants and personnel (performance bias)
Serious adverse events

High risk

Open-label

Blinding of participants and personnel (performance bias)
Treatment-related deaths

Low risk

Objective outcome

Blinding of outcome assessment (detection bias) Pathological complete response | Low risk | Two subspecialized breast pathologists independently reviewed whole slide scans (blinded to each other, treatment status, and time point).
Blinding of outcome assessment (detection bias) Serious adverse events | High risk | Open-label
Blinding of outcome assessment (detection bias) Treatment-related deaths | Low risk | Objective outcome

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data 8.96%

Selective reporting (reporting bias) | Unclear risk | Some outcomes were pre-specified and some without information
Other bias | Low risk | No other bias

NeoTRIP
Study characteristics

Methods

Accrual time: May 2016 to December 2018
Phase III RCT
Multicentre
Countries: Austria, Germany, Ireland, Italy, Russia, Spain, China
Median follow-up: not reported

Participants

Sample size: 280
Median age: 49.5 years in atezolizumab plus chemotherapy group; 50 years in chemotherapy group
Inclusion criteria: patients were eligible if they had a previously untreated histologically confirmed unilateral breast cancer with invasive ductal histology not otherwise specified of high proliferation or grade, HER2 negative and oestrogen and progesterone receptor negative. A central histology assessment of core biopsies for hormone receptor and HER2 status and determination of PD-L1 expression immune cell (IC) testing was mandatory. PD-L1 expression was measured with the VENTANA SP142 assay (Ventana Medical Systems, Inc.; Roche Tissue Diagnostics, an Affiliate of Roche, Tucson, AZ). Patients had to be aged 18 years or older with an Eastern Cooperative Oncology Group performance status ≤1. The tumour had to be classified as early high risk (T1cN1; T2N1; T3N0) versus locally advanced (T3N1; T4a, b, c; T4d any N; any T and N2-3).
Exclusion criteria: metastatic disease (stage IV), bilateral breast cancer, other malignancies, inadequate bone marrow or renal function, impaired liver function, impaired cardiac function, uncontrolled hypertension, pregnancy, refusal to use contraception, and history of autoimmune disease.

Interventions

Intervention arm: neoadjuvant carboplatin area under the curve 2 and nab-paclitaxel 125 mg/m^2 i.v. on days 1 and 8 with atezolizumab 1200 mg i.v. on day 1; every 3 weeks for 8 cycles
Control arm: neoadjuvant carboplatin area under the curve 2 and nab-paclitaxel 125 mg/m^2 i.v. on days 1 and 8; every 3 weeks for 8 cycles

Outcomes

Primary outcome
Pathological complete response: absence of invasive cells in breast and lymph nodes
Secondary outcomes
Any adverse events: according to the NCI CTCAE version 4.0
SAEs: according to the NCI CTCAE version 4.0
Treatment-related deaths

Notes

Trials registration link: https://clinicaltrials.gov/study/NCT02620280
All randomised participants were included in the intention-to-treat analysis.
Funding support: supported by Fondazione Michelangelo and by unrestricted grants and free study drugs from Hoffman-La Roche, Ltd, Switzerland and Celgene, a Bristol Myers Squibb Company, Switzerland; supported in part by a Breast Cancer Research Foundation grant to LG

Risk of bias
Bias | Authors' judgement Support for judgement

NeoTRIP (Continued)
Random sequence generation (selection bias) | Low risk | Randomisation was done centrally via computer-generated blocks and stratification was by geographical area, disease stage (early high risk versus locally advanced) and PD-L1 expression in IC testing versus no.
Allocation concealment (selection bias) | Low risk | Central randomisation

Blinding of participants and personnel (performance bias)
Pathological complete response

Low risk

Pathological complete response was assessed by local pathologist according to provided guidelines requiring examination on serial sections of the surgical specimen. Blinding of participants and personnel is generally not a concern

Blinding of participants and personnel (performance bias)
Any adverse events

Low risk

Toxicity reported adverse events will be categorized according
to the NCI-CTCAE version 4.0. Blinding of participants and personnel is generally not a concern

Blinding of participants and personnel (performance bias)
Serious adverse events

Low risk

Toxicity reported adverse events will be categorized according
to the NCI-CTCAE version 4.0. Blinding of participants and personnel is generally not a concern

Blinding of participants and personnel (performance bias)
Treatment-related deaths

Low risk

Objective outcome

Blinding of outcome assessment (detection bias) Pathological complete response | Low risk | Pathological complete response was assessed by local pathologist according to provided guidelines requiring examination on serial sections of the surgical specimen.
Blinding of outcome assessment (detection bias) Any adverse events | Low risk | Toxicity reported adverse events will be categorized according to the NCI-CTCAE version 4.0.
Blinding of outcome assessment (detection bias) Serious adverse events | Low risk | Toxicity reported adverse events will be categorized according to the NCI-CTCAE version 4.0.
Blinding of outcome assessment (detection bias) Treatment-related deaths | Low risk | Objective outcome

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data 8.21%

Selective reporting (reporting bias) | Low risk | All outcomes were pre-specified
Other bias | Low risk | No other bias

EFS: event-free survival
ER-: oestrogen receptor-negative
HER2: human epidermal growth factor receptor 2
HRQoL: health-related quality of life

IHC: immunohistochemistry
i.v.: intravenously
NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events
OS: overall survival
PR: progesterone receptor
RCT: randomised controlled trial
SAEs: serious adverse events
sTILs: stromal tumour-infiltrating lymphocytes
TNBC: triple-negative breast cancer
Characteristics of excluded studies [ordered by study ID]
Study | Reason for exclusion
ACTRN12617000651381 | Not RCT
ACTRN12619001308189 | No eligible comparison
ChiCTR2100041675 | Not RCT
EUCTR2018-001155-13 | No results/data are available
Fehrenbacher 2020 | Not PD-1 or PD-L1 inhibitors
Foldi 2022 | Not RCT
Khoury 2019 | Previously treated with neoadjuvant chemotherapy
NCT02322814 | Not early triple-negative breast cancer
NCT02530489 | Not RCT
NCT02622074 | No eligible comparison
NCT02685059 | Registered record of published trial, no result
NCT03036488 | Registered record of published trial, no result
NCT03251313 | Not RCT
NCT03281954 | Not early triple-negative breast cancer
NCT03487666 | Previously treated with neoadjuvant chemotherapy
NCT03639948 | Not RCT
NCT03719326 | Not early triple-negative breast cancer
NCT03756298 | Previously treated with neoadjuvant chemotherapy
NCT04191135 | Not early triple-negative breast cancer
NCT04331067 | No eligible comparison
NCT04809779 | Not RCT
NCT05088057 | Not RCT

| Cochrane Library | Trusted evidence. Informed decisions. Better health. | Cochrane Database of Systematic Reviews
Study | Reason for exclusion |
NCT05215106 | Not RCT |
NCT05556200 | Not RCT |
NCT05681728 | Not RCT |
NCT05877859 | Not RCT |
NCT06604858 | Not RCT |
Pusztai 2024 | Wrong outcome |
Schmid 2020 | No eligible comparison |

RCT: randomised controlled trial
Characteristics of studies awaiting classification [ordered by study ID]
NCT03356860

Methods

Accrual time: April 2017 to January 2024
Phase I and II RCT
Multicentre
Country: Belgium

Participants

Sample size: 57
Inclusion criteria:
•		Written informed consent and any locally required authorisation (EU Data Privacy Directive in the EU) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations
•		Female and male aged > 18 years at time of study entry
•		Patient has T1-T4 any N, M0, operable breast cancer
•		Confirmed invasive ductal, lobular, mixed or medullary breast carcinoma
•		TNBC, defined as negative oestrogen and progesterone receptors as per local laboratory testing and negative HER2 defined as negative ISH test or an IHC status of 0 or 1+ as per local laboratory testing
•		Luminal B HER2 negative BC, defined as positive oestrogen and/or progesterone receptors, a negative HER2 defined as negative ISH test or an IHC status of 0 or 1+ as per local laboratory testing and a Ki67 > 14%.
•		World Health Organization (WHO) performance status of 0 or 1
•		Adequate normal organ and marrow function as defined below:
◦		Haemoglobin ≥ 9.0 g/dL
◦		Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)
◦		Platelet count ≥ 100 x 109/L (>100,000 per mm3)
◦		Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
◦		AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit
◦		Serum creatinine clearance >40 mL/min
• Normal cardiac function must be confirmed by ECG and cardiac function assessed by US imagery, radionucleotide ventriculography or MUGA, 4 weeks prior to randomisation. Results must be above the normal limit of the institution.

•		Women must either be postmenopausal or must have a negative serum pregnancy test 14 days upon study entry.
•		For a woman of childbearing potential, an effective method of birth control must be employed.
•		Men must use 2 effective contraceptive measures or male sterilisation with female partners of childbearing potential or pregnant female partners, or they must remain abstinent during the treatment period and for at least 6 months after the last dose of the study treatment.
•		Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.
•		Patient accepts planned biological samples collection and their use for the trial propose.
Exclusion criteria:
•		Involvement in the planning and/or conduct of the study
•		Previous enrolment in the present study
•		Participation in another clinical study with an investigational product during the last 4 weeks
•		Patient has locally recurrent or metastatic invasive BC
•		History of another primary malignancy except for:
◦		malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug;
◦		adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
◦		adequately treated carcinoma in situ without evidence of disease, e.g. cervical cancer in situ or BC in situ.
•		Patient has received any systemic therapy (e.g. chemotherapy, targeted therapy, immunotherapy) or radiotherapy for current breast cancer disease
•		Whatever the indication, receipt of a last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolisation, monoclonal antibodies, other investigational agent) ≤ 21 days prior to the first dose of study drug
•		Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab
•		Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1
•		Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
•		Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from ECGs using Fridericia's Correction
•		Known or suspected congestive heart failure (>NYHA I) and/or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP >140/90 mm Hg under treatment with 2 antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease
•		Active or prior documented autoimmune disease within the past 2 years NOTE: patients with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
•		Active or prior documented inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis)
•		History of primary immunodeficiency
•		History of allogeneic organ transplant
•		History of hypersensitivity to durvalumab or any excipient
•		Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, any patient known to have evidence of acute or chronic hepatitis B, hepatitis C or HIV, or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent
•		Patients with uncontrolled seizures
•		Known history of active tuberculosis

NCT03356860 (Continued)

•		Anticipation that a live-attenuated vaccine will be required during the period from 30 days prior to the first planned durvalumab administration (e.i. week 18 and week 14 after study entry for the phase Ib and phase II respectively) to 5 months of durvalumab discontinuation. Influenza vaccination (inactivated forms only but not live-attenuated forms) should be given during influenza season only (approximately October to March).
•		Female patients who are pregnant, breastfeeding, or female patients of reproductive potential who are not employing an effective method of birth control
•		Men with female partners of childbearing potential or pregnant female partners who are not employing an effective method of birth control
•		Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results

Interventions

Intervention arm: paclitaxel 80 mg/m^2 i.v. weekly from week 1 to 12 and then an association of epirubicin 90 mg/m^2 i.v. and cyclophosphamide 600 mg/m^2 i.v. every 2 weeks from week 14 to 20 and durvalumab 1500 mg i.v. at week 14 and week 18
Control arm: paclitaxel 80 mg/m^2 i.v. weekly from week 1 to 12 and then an association of epiru- bicin 90 mg/m^2 i.v. and cyclophosphamide 600 mg/m^2 i.v. every 2 weeks from week 14 to 20

Outcomes

Primary outcome
Pathological complete response
Secondary outcomes
Adverse events
SAEs

Notes

Trials registration link: https://clinicaltrials.gov/study/NCT03356860
Funding support: Grand Hôpital de Charleroi

ALT (SGPT): alanine aminotransferase (serum glutamic-pyruvic transaminase)
AST (SGOT): aspartate aminotransferase (serum glutamic-oxaloacetic transaminase)
BC: breast cancer
BP: blood pressure
ECG: electrocardiogram
IHC: immunohistochemistry
ISH: in situ hybridisation
i.v.: intravenous
MUGA: multigated acquisition scan
NYHA: New York Heart Association
RCT: randomised controlled trial
SAEs: serious adverse events
TNBC: triple-negative breast cancer
Characteristics of ongoing studies [ordered by study ID]
NCT04301739
Study name | A Randomized, Double-Blind, International Multi-Centre, Phase III Clinical Study to Evaluate Efficacy and Safety of HLX10 in Combination With Chemotherapy Versus Placebo in Combination With Chemotherapy as Neoadjuvant Therapy and HLX10 Versus Placebo as Adjuvant Therapy in Patients With Triple Negative Breast Cancer (TNBC)

Methods

Accrual time: April 2020 to April 2027
Phase III RCT, double-blind

NCT04301739 (Continued) | Country: China

Participants

Sample size: 522
Inclusion criteria:
•		Patients histologically diagnosed with previously untreated TNBC (lack of human epidermal growth factor receptor-2 (HER2), oestrogen receptor (ER), progesterone receptor expression as determined by the study site)
•		Patients who are judged as one of the following by the American Joint Committee on Cancer (AJCC) within 4 weeks prior to randomisation:
◦		T1c, N1-N2, M0
◦		T2, N0-N2, M0
◦		T3, N0-N2, M0
◦		T4a-c, N0-N2, M0
•		Major organs are functioning well
•		Patient must keep contraception
Exclusion criteria:
•		Patients with any other active malignancy within 5 years prior to signing the informed consent form or at the same time. Localised tumours that have been cured such as basal cell carcinoma, squamous-cell skin cancer, superficial bladder carcinoma, and cervical cancer in situ are acceptable.
•		Patients who have received chemotherapy, targeted therapy, or radiotherapy within 12 months prior to the initial dose of the investigational product
•		Patients with a history of severe allergy to any monoclonal antibody or investigational product and its excipient
•		Pregnant or lactating women
•		Patients with a known history of psychotropics abuse or drug abuse
•		Patients presenting other factors not suitable for participation as judged by the investigator

Interventions

Intervention arm: HLX10 + chemotherapy (nab-paclitaxel carboplatin) for 4 cycles, followed by HLX10 + chemotherapy (doxorubicin or epirubicin cyclophosphamide) for 4 cycles; after surgery, HLX10 for 9 cycles
Control arm: placebo + chemotherapy (nab-paclitaxel carboplatin) for 4 cycles, followed by placebo + chemotherapy (doxorubicin or epirubicin cyclophosphamide) for 4 cycles; after surgery, placebo for 9 cycles

Outcomes

Primary outcome
Pathological complete response (ypT0/Tis, ypN0): assessed by central pathology laboratory based on American Joint Committee on Cancer (AJCC) staging system

Starting date | April 2020
Contact information | olivia_chi@henlius.com.cn; weizhen_liu@henlius.com.cn

Notes

Trials registration link: https://clinicaltrials.gov/study/NCT04301739
Funding support: Shanghai Henlius Biotech

RCT: randomised controlled trial
TNBC: triple-negative breast cancer
D A T A A N D A N A L Y S E S
Comparison 1. PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size
1.1 Pathological complete response | 6 | 1564 | Risk Ratio (IV, Random, 95% CI) | 1.47 [1.15, 1.86]
1.2 Event-free survival | 4 | | Hazard Ratio (IV, Random, 95% CI) | 0.64 [0.52, 0.79]
1.3 Overall survival | 3 | | Hazard Ratio (IV, Random, 95% CI) | 0.56 [0.34, 0.93]
1.4 Health-related quality of life | 2 | 1395 | Mean Difference (IV, Random, 95% CI) | -1.49 [-3.88, 0.91]
1.5 Any adverse events | 3 | 1781 | Odds Ratio (IV, Random, 95% CI) | 0.26 [0.05, 1.24]
1.6 Serious adverse events | 5 | 2016 | Odds Ratio (IV, Random, 95% CI) | 1.75 [1.15, 2.67]
1.7 Treatment-related deaths | 4 | 1761 | Risk Difference (IV, Random, 95% CI) | 0.00 [-0.00, 0.01]

Analysis 1.1. Comparison 1: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy
vs neoadjuvant chemotherapy, Outcome 1: Pathological complete response

Study or Subgroup

PD-1/PD-L1 inhibitors plus NACT

NACT
Events Total

Weight

Risk Ratio
IV, Random, 95% CI

Risk Ratio
IV, Random, 95% CI

| Events | Total | | | |
GeparNuevo | 47 | 88 | 38	86 | 18.3% | 1.21 [0.89 , 1.64] | |
I-SPY2 | 19 | 28 | 17	80 | 12.4% | 3.19 [1.95 , 5.23] | |
IMpassion031 | 95 | 165 | 69	168 | 21.3% | 1.40 [1.12 , 1.75] | |
KEYNOTE-522 | 260 | 401 | 103	201 | 23.6% | 1.27 [1.09 , 1.47] | |
NCI 10013 | 25 | 45 | 3	22 | 4.1% | 4.07 [1.38 , 12.04] | |
NeoTRIP | 67 | 138 | 63	142 | 20.3% | 1.09 [0.85 , 1.41] | |
Total (Walda) | | 865 | 699 | 100.0% | 1.47 [1.15 , 1.86] | |
Total events: | 513 | | 293 | | | |
Test for overall effect: Z | = 3.13 (P = 0.002) | | | | 0.01 | 0.1 | 1	10	100
| | | | | Favours NACT | Favours PD-1/PD-L1 inhibitors plus NACT
Heterogeneity: Tau² (DLb) = 0.06; Chi² = 19.51, df = 5 (P = 0.002); I² = 74%
Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.

Analysis 1.2. Comparison 1: PD-1 or PD-L1 inhibitors plus neoadjuvant
chemotherapy vs neoadjuvant chemotherapy, Outcome 2: Event-free survival

Study or Subgroup

log[Hazard Ratio]

SE

Weight

Hazard Ratio
IV, Random, 95% CI

Hazard Ratio
IV, Random, 95% CI

GeparNuevo | -0.733969 | 0.357608 | 9.0% | 0.48 [0.24 , 0.97] | | |
I-SPY2 | -0.510826 | 0.4313 | 6.2% | 0.60 [0.26 , 1.40] | | |
IMpassion031 | -0.274437 | 0.326775 | 10.7% | 0.76 [0.40 , 1.44] | | |
KEYNOTE-522 | -0.430783 | 0.124241 | 74.2% | 0.65 [0.51 , 0.83] | | |
Total (Walda) | | | 100.0% | 0.64 [0.52 , 0.79] | | |
Test for overall effect: Z | = 4.17 (P < 0.0001) | | | 0.01 | 0.1 | 10 | 100
| | | Favours PD-1/PD-L1 inhibitors plus NACT | Favours NACT
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.96, df = 3 (P = 0.81); I² = 0%

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.
Analysis 1.3. Comparison 1: PD-1 or PD-L1 inhibitors plus neoadjuvant
chemotherapy vs neoadjuvant chemotherapy, Outcome 3: Overall survival
| Hazard Ratio	Hazard Ratio
Study or Subgroup | log[Hazard Ratio]	SE	Weight IV, Random, 95% CI	IV, Random, 95% CI

GeparNuevo	-1.427116	0.560527	16.8%	0.24 [0.08 ,	0.72]
IMpassion031	-0.371064	0.507818	19.6%	0.69 [0.26 ,	1.87]
KEYNOTE-522	-0.415515	0.1413	63.6%	0.66 [0.50 ,	0.87]
Total (Walda)	100.0%	0.56 [0.34 , 0.93]

Test for overall effect: Z = 2.22 (P = 0.03)	_0.01	_0.1	_1	_10	_100
Favours PD-1/PD-L1 inhibitors plus NACT Favours NACT

Heterogeneity: Tau² (DLb) = 0.09; Chi² = 3.10, df = 2 (P = 0.21); I² = 36%
Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.
Analysis 1.4. Comparison 1: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy
vs neoadjuvant chemotherapy, Outcome 4: Health-related quality of life
| PD-1/PD-L1 inhibitors plus NACT	NACT	Mean Difference	Mean Difference
Study or Subgroup | Mean	SD	Total	Mean	SD	Total Weight IV, Random, 95% CI	IV, Random, 95% CI

IMpassion031
KEYNOTE-522

-4.5	26.824026	161	-1.65	27.883159	167	16.4%	-2.85 [-8.77 , 3.07]
-11.24	21.306712	701	-10.02	20.430043	366	83.6%	-1.22 [-3.84 , 1.40]

Total (Walda) | 862	533 100.0%	-1.49 [-3.88 , 0.91]
Test for overall effect: Z = 1.22 (P = 0.22)
-100	-50	0	50	100
Favours NACT Favours PD-1/PD-L1 inhibitors plus NACT

Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.24, df = 1 (P = 0.62); I² = 0%
Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.
Analysis 1.5. Comparison 1: PD-1 or PD-L1 inhibitors plus neoadjuvant
chemotherapy vs neoadjuvant chemotherapy, Outcome 5: Any adverse events

Study or Subgroup

PD-1/PD-L1 inhibitors plus NACT

NACT
Events Total

Weight

Odds Ratio
IV, Random, 95% CI

Odds Ratio
IV, Random, 95% CI

| Events | Total | | | |
IMpassion031 | 163 | 164 | 167	167 | 23.6% | 0.33 [0.01 , 8.05] | |
KEYNOTE-522 | 777 | 783 | 389	389 | 29.4% | 0.15 [0.01 , 2.73] | |
NeoTRIP | 135 | 138 | 139	140 | 47.0% | 0.32 [0.03 , 3.15] | |
Total (Walda) | | 1085 | 696 | 100.0% | 0.26 [0.05 , 1.24] | |
Total events: | 1075 | | 695 | | | |
Test for overall effect: Z | = 1.69 (P = 0.09) | | | | 0.01 | 0.1 | 1	10	100
| | | | Favours PD-1/PD-L1 inhibitors plus NACT | Favours NACT
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.18, df = 2 (P = 0.91); I² = 0%

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.
Analysis 1.6. Comparison 1: PD-1 or PD-L1 inhibitors plus neoadjuvant
chemotherapy vs neoadjuvant chemotherapy, Outcome 6: Serious adverse events

Study or Subgroup

PD-1/PD-L1 inhibitors plus NACT

NACT
Events Total

Weight

Odds Ratio
IV, Random, 95% CI

Odds Ratio
IV, Random, 95% CI

| Events | Total | | | |
GeparNuevo | 30 | 92 | 29	82 | 20.6% | 0.88 [0.47 , 1.66] | |
IMpassion031 | 50 | 164 | 30	167 | 24.1% | 2.00 [1.20 , 3.36] | |
KEYNOTE-522 | 267 | 783 | 78	389 | 32.0% | 2.06 [1.55 , 2.75] | |
NCI 10013 | 10 | 45 | 4	16 | 8.0% | 0.86 [0.23 , 3.25] | |
NeoTRIP | 25 | 138 | 8	140 | 15.3% | 3.65 [1.58 , 8.41] | |
Total (Walda) | | 1222 | 794 | 100.0% | 1.75 [1.15 , 2.67] | |
Total events: | 382 | | 149 | | | |
Test for overall effect: Z | = 2.59 (P = 0.010) | | | | 0.01 | 0.1 | 1	10	100
| | | | Favours PD-1/PD-L1 inhibitors plus NACT | Favours NACT
Heterogeneity: Tau² (DLb) = 0.12; Chi² = 9.75, df = 4 (P = 0.04); I² = 59%

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.
Analysis 1.7. Comparison 1: PD-1 or PD-L1 inhibitors plus neoadjuvant
chemotherapy vs neoadjuvant chemotherapy, Outcome 7: Treatment-related deaths
PD-1/PD-L1 inhibitors plus NACT NACT	Risk Difference	Risk Difference
Study or Subgroup	Events	Total Events Total Weight IV, Random, 95% CI	IV, Random, 95% CI
I-SPY2 | 0 | 69 | 0 | 181 | 8.2% | 0.00 [-0.02 , 0.02] | |
KEYNOTE-522 | 4 | 783 | 1 | 389 | 72.6% | 0.00 [-0.00 , 0.01] | |
NCI 10013 | 0 | 45 | 0 | 16 | 0.5% | 0.00 [-0.09 , 0.09] | |
NeoTRIP | 0 | 138 | 0 | 140 | 18.7% | 0.00 [-0.01 , 0.01] | |
Total (Walda) Total events: | 4 | 1035 | 1 | 726 | 100.0% | 0.00 [-0.00 , 0.01] | |
Test for overall effect: Z = 0.60 (P = 0.55) | -100	-50 | 0 | 50	100
| Favours PD-1/PD-L1 inhibitors plus NACT | | Favours NACT
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.13, df = 3 (P = 0.99); I² = 0%
Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.

Comparison 2. PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy – subgroup analysis by type of immune checkpoint inhibitors
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size
2.1 Pathological complete | 6 | 1564 | Risk Ratio (IV, Random, 95% CI) | 1.47 [1.15, 1.86]
response | | | |
2.1.1 PD-1 inhibitors | 2 | 710 | Risk Ratio (IV, Random, 95% CI) | 1.95 [0.79, 4.82]
2.1.2 PD-L1 inhibitors | 4 | 854 | Risk Ratio (IV, Random, 95% CI) | 1.30 [1.02, 1.66]
2.2 Event-free survival | 4 | | Hazard Ratio (IV, Random, 95% CI) | 0.64 [0.52, 0.79]
2.2.1 PD-1 inhibitors | 2 | | Hazard Ratio (IV, Random, 95% CI) | 0.65 [0.51, 0.82]
2.2.2 PD-L1 inhibitors | 2 | | Hazard Ratio (IV, Random, 95% CI) | 0.62 [0.38, 0.99]
2.3 Overall survival | 3 | | Hazard Ratio (IV, Random, 95% CI) | 0.56 [0.34, 0.93]
2.3.1 PD-1 inhibitors | 1 | | Hazard Ratio (IV, Random, 95% CI) | 0.66 [0.50, 0.87]
2.3.2 PD-L1 inhibitors | 2 | | Hazard Ratio (IV, Random, 95% CI) | 0.42 [0.15, 1.17]
2.4 Health-related quality | 2 | 1395 | Mean Difference (IV, Random, 95% CI) | -1.49 [-3.88, 0.91]
of life | | | |
2.4.1 PD-1 inhibitors | 1 | 1067 | Mean Difference (IV, Random, 95% CI) | -1.22 [-3.84, 1.40]
2.4.2 PD-L1 inhibitors | 1 | 328 | Mean Difference (IV, Random, 95% CI) | -2.85 [-8.77, 3.07]
2.5 Any adverse events | 3 | 1781 | Odds Ratio (IV, Random, 95% CI) | 0.26 [0.05, 1.24]
2.5.1 PD-1 inhibitors | 1 | 1172 | Odds Ratio (IV, Random, 95% CI) | 0.15 [0.01, 2.73]
2.5.2 PD-L1 inhibitors | 2 | 609 | Odds Ratio (IV, Random, 95% CI) | 0.32 [0.05, 2.07]
Immune checkpoint inhibitors and chemotherapy versus chemotherapy for early triple-negative breast cancer (Review) | 49
Copyright © 2026 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size
2.6 Serious adverse events | 5 | 2016 | Odds Ratio (IV, Random, 95% CI) | 1.75 [1.15, 2.67]
2.6.1 PD-1 inhibitors | 1 | 1172 | Odds Ratio (IV, Random, 95% CI) | 2.06 [1.55, 2.75]
2.6.2 PD-L1 inhibitors | 4 | 844 | Odds Ratio (IV, Random, 95% CI) | 1.61 [0.84, 3.07]
2.7 Treatment-related deaths | 4 | 1761 | Risk Difference (IV, Random, 95% CI) | 0.00 [-0.00, 0.01]
2.7.1 PD-1 inhibitors | 2 | 1422 | Risk Difference (IV, Random, 95% CI) | 0.00 [-0.00, 0.01]
2.7.2 PD-L1 inhibitors | 2 | 339 | Risk Difference (IV, Random, 95% CI) | 0.00 [-0.01, 0.01]

Analysis 2.1. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant
chemotherapy vs neoadjuvant chemotherapy – subgroup analysis by type of
immune checkpoint inhibitors, Outcome 1: Pathological complete response

PD-1/PD-L1 inhibitors plus NACT	NACT
Study or Subgroup	Events	Total	Events Total

Weight

Risk Ratio
IV, Random, 95% CI

Risk Ratio
IV, Random, 95% CI

2.1.1 PD-1 inhibitors
I-SPY2	19	28
KEYNOTE-522	260	401
Subtotal (Walda)	429
Total events:	279
Test for overall effect: Z = 1.44 (P = 0.15)
Heterogeneity: Tau² (DLb) = 0.39; Chi² = 12.36, df = 1 (P = 0.0004); I²

17
103
120
= 92%

80
201
281

12.4%
23.6%
36.0%

3.19 [1.95 , 5.23]
1.27 [1.09 , 1.47]
1.95 [0.79 , 4.82]

2.1.2 PD-L1 inhibitors
GeparNuevo	47	88	38
IMpassion031	95	165	69
NCI 10013	25	45	3
NeoTRIP	67	138	63
Subtotal (Walda)	436
Total events:	234	173
Test for overall effect: Z = 2.14 (P = 0.03)
Heterogeneity: Tau² (DLb) = 0.03; Chi² = 6.64, df = 3 (P = 0.08); I² = 55%

86
168
22
142
418

18.3%
21.3%
4.1%
20.3%
64.0%

1.21 [0.89 , 1.64]
1.40 [1.12 , 1.75]
4.07 [1.38 , 12.04]
1.09 [0.85 , 1.41]
1.30 [1.02 , 1.66]

Total (Walda)	865
Total events:	513

293

699

100.0%

1.47 [1.15 , 1.86]

Test for overall effect: Z = 3.13 (P = 0.002) Test for subgroup differences: Chi² = 0.71, df = 1 (P = 0.40), I² = 0% | | | | | 0.01	0.1 Favours NACT | 10	100 Favours PD-1/PD-L1 inhibitors plus NACT
Heterogeneity: Tau² (DLb) = 0.06; Chi² = 19.51, df = 5 (P = 0.002); I² = 74%

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.

Analysis 2.2. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant
chemotherapy – subgroup analysis by type of immune checkpoint inhibitors, Outcome 2: Event-free survival

Study or Subgroup	log[Hazard Ratio]

SE	Weight IV

Hazard Ratio
, Random, 95% CI

Hazard Ratio
IV, Random, 95% CI

2.2.1 PD-1 inhibitors
I-SPY2	-0.510826
KEYNOTE-522	-0.430783
Subtotal (Walda)
Test for overall effect: Z = 3.66 (P = 0.0003)
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.03, df

0.4313	6.2%
0.124241	74.2%
80.3%
= 1 (P = 0.86); I² = 0%

0.60 [0.26 , 1.40]
0.65 [0.51 , 0.83]
0.65 [0.51 , 0.82]

2.2.2 PD-L1 inhibitors
GeparNuevo	-0.733969
IMpassion031	-0.274437
Subtotal (Walda)
Test for overall effect: Z = 2.00 (P = 0.05)
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.90, df

0.357608	9.0%
0.326775	10.7%
19.7%
= 1 (P = 0.34); I² = 0%

0.48 [0.24 , 0.97]
0.76 [0.40 , 1.44]
0.62 [0.38 , 0.99]

Total (Walda) | 100.0% | 0.64 [0.52 , 0.79] | |

Test for overall effect: Z = 4.17 (P < 0.0001)
Test for subgroup differences: Chi² = 0.03, df = 1 (P = 0.86), I² = 0%

0.01	0.1
Favours PD-1/PD-L1 inhibitors plus NACT

10	100
Favours NACT

Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.96, df = 3 (P = 0.81); I² = 0%

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.
Analysis 2.3. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant
chemotherapy – subgroup analysis by type of immune checkpoint inhibitors, Outcome 3: Overall survival

Hazard Ratio
IV, Random, 95% CI

Hazard Ratio
Study or Subgroup log[Hazard Ratio] SE Weight IV, Random, 95% CI

2.3.1 PD-1 inhibitors
KEYNOTE-522	-0.415515
Subtotal
Test for overall effect: Z = 2.94 (P = 0.003)
Heterogeneity: Not applicable

0.1413

63.6%
63.6%

2.3.2 PD-L1 inhibitors | |
GeparNuevo	-1.427116 | 0.560527 | 17.0%
IMpassion031	-0.371064 | 0.513334 | 19.4%
Subtotal (Walda) | | 36.4%
Test for overall effect: Z = 1.66 (P = 0.10) | |
Heterogeneity: Tau² (DLb) = 0.27; Chi² = 1.93, df | = 1 (P = 0.16); I² = 48%
Total (Walda) | | 100.0%

Test for overall effect: Z = 2.22 (P = 0.03)
Test for subgroup differences: Chi² = 0.71, df = 1 (P = 0.40), I² = 0%
Heterogeneity: Tau² (DLb) = 0.09; Chi² = 3.10, df = 2 (P = 0.21); I² = 36%

0.66 [0.50 , 0.87]
0.66 [0.50 , 0.87]

0.24 [0.08 , 0.72] |
0.69 [0.25 , 1.89] |
0.42 [0.15 , 1.17] |
0.56 [0.34 , 0.93] |
0.01	0.1 | 10	100
Favours PD-1/PD-L1 inhibitors plus NACT | Favours NACT

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.

Analysis 2.4. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant
chemotherapy vs neoadjuvant chemotherapy – subgroup analysis by type
of immune checkpoint inhibitors, Outcome 4: Health-related quality of life

PD-1/PD-L1 inhibitors plus NACT

NACT SD

Total

Weight

Mean Difference
IV, Random, 95% CI

Mean Difference
IV, Random, 95% CI

Study or Subgroup	Mean | SD | Total | Mean | | | | |

2.4.1 PD-1 inhibitors
KEYNOTE-522	-11.24
Subtotal
Test for overall effect: Z = 0.91 (P = 0.36)
Heterogeneity: Not applicable

21.306712

701
701

-10.02

20.430043

366
366

83.6%
83.6%

-1.22 [-3.84 , 1.40]
-1.22 [-3.84 , 1.40]

2.4.2 PD-L1 inhibitors
IMpassion031	-4.5
Subtotal
Test for overall effect: Z = 0.94 (P = 0.35)
Heterogeneity: Not applicable

26.824026

161
161

-1.65

27.883159

167
167

16.4%
16.4%

-2.85 [-8.77 , 3.07]
-2.85 [-8.77 , 3.07]

Total (Walda) | | 862 | | | 533 | 100.0% | -1.49 [-3.88 , 0.91] | |
Test for overall effect: Z = 1.22 (P = 0.22)	_-100	_-50	_0	_50	_100
Test for subgroup differences: Chi² = 0.24, df = 1 (P = 0.62), I² = 0%	Favours NACT Favours PD-1/PD-L1 inhibitors plus NACT
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.24, df = 1 (P = 0.62); I² = 0%

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.
Analysis 2.5. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant
chemotherapy – subgroup analysis by type of immune checkpoint inhibitors, Outcome 5: Any adverse events

PD-1/PD-L1 inhibitors
Study or Subgroup	Events

plus NACT Total

NACT
Events Total

2.5.1 PD-1 inhibitors | | |
KEYNOTE-522	777 | 783 | 389 | 389

Subtotal
Total events:	777
Test for overall effect: Z = 1.28 (P = 0.20)
Heterogeneity: Not applicable
2.5.2 PD-L1 inhibitors

783

389

389

I-SPY2	163 | 164 | 167 | 167
NeoTRIP	135 | 138 | 139 | 140

Subtotal (Walda)
Total events:	298
Test for overall effect: Z = 1.19 (P = 0.23)

302

306

307

Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.00, df = | 1 (P = 1.00); I² | = 0% |

Total (Walda)
Total events:	1075

1085

695

696

Odds Ratio	Odds Ratio
Weight IV, Random, 95% CI	IV, Random, 95% CI

Test for overall effect: Z = 1.69 (P = 0.09)
Test for subgroup differences: Chi² = 0.18, df = 1 (P = 0.67), I² = 0%
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.18, df = 2 (P = 0.91); I² = 0%

29.4%	0.15 [0.01 , 2.73]
29.4%	0.15 [0.01 , 2.73]

23.6%	0.33 [0.01 ,	8.05]
47.0%	0.32 [0.03 ,	3.15]
70.6%	0.32 [0.05 ,	2.07]
100.0%	0.26 [0.05 ,	1.24]

0.01	0.1
Favours PD-1/PD-L1 inhibitors plus NACT

10	100
Favours NACT

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.

Analysis 2.6. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant
chemotherapy – subgroup analysis by type of immune checkpoint inhibitors, Outcome 6: Serious adverse events

Study or Subgroup

PD-1/PD-L1 inhibitors plus NACT

NACT
Events Total

| Events | Total |
2.6.1 PD-1 inhibitors | | |
KEYNOTE-522 | 267 | 783 | 78	389
Subtotal | | 783 | 389
Total events: | 267 | | 78
Test for overall effect: Z | = 4.91 (P < 0.00001) | |
Heterogeneity: Not applicable | |
2.6.2 PD-L1 inhibitors | | |
GeparNuevo | 30 | 92 | 29	82
IMpassion031 | 50 | 164 | 30	167
NCI 10013 | 10 | 45 | 4	16
NeoTRIP | 25 | 138 | 8	140
Subtotal (Walda) | | 439 | 405
Total events: | 115 | | 71

Test for overall effect: Z = 1.44 (P = 0.15)
Heterogeneity: Tau² (DLb) = 0.27; Chi² = 8.73, df = 3 (P = 0.03); I² = 66%

Total (Walda) | 1222 | 794
Total events: | 382 | 149 |

Test for overall effect: Z = 2.59 (P = 0.010)
Test for subgroup differences: Chi² = 0.48, df = 1 (P = 0.49), I² = 0%
Heterogeneity: Tau² (DLb) = 0.12; Chi² = 9.75, df = 4 (P = 0.04); I² = 59%

Weight

Odds Ratio
IV, Random, 95% CI

Odds Ratio
IV, Random, 95% CI

32.0% | 2.06 [1.55 , 2.75] |
32.0% | 2.06 [1.55 , 2.75] |
20.6% | 0.88 [0.47 , 1.66] |
24.1% | 2.00 [1.20 , 3.36] |

8.0%
15.3%

0.86 [0.23 , 3.25]
3.65 [1.58 , 8.41]

68.0% | 1.61 [0.84 , 3.07] |
100.0% | 1.75 [1.15 , 2.67] |
| 0.01 | 0.1	1	10	100
Favours PD-1/PD-L1 inhibitors plus NACT	Favours NACT

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.
Analysis 2.7. Comparison 2: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant
chemotherapy – subgroup analysis by type of immune checkpoint inhibitors, Outcome 7: Treatment-related deaths
PD-1/PD-L1 inhibitors plus NACT NACT	Risk Difference	Risk Difference
Study or Subgroup	Events	Total Events Total Weight IV, Random, 95% CI	IV, Random, 95% CI
2.7.1 PD-1 inhibitors | | | | | |
I-SPY2	0	69 | 0 | 181 | 8.2% | 0.00 [-0.02 , 0.02] | |
KEYNOTE-522	4	783 | 1 | 389 | 72.6% | 0.00 [-0.00 , 0.01] | |
Subtotal (Walda)	852 | | 570 | 80.8% | 0.00 [-0.00 , 0.01] | |
Total events:	4 | 1 | | | | |

Test for overall effect: Z = 0.67 (P = 0.51)
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.05, df = 1 (P = 0.82); I² = 0%

2.7.2 PD-L1 inhibitors | | | | | |
NCI 10013	0	45 | 0 | 16 | 0.5% | 0.00 [-0.09 , 0.09] | |
NeoTRIP	0	138 | 0 | 140 | 18.7% | 0.00 [-0.01 , 0.01] | |
Subtotal (Walda)	183 | | 156 | 19.2% | 0.00 [-0.01 , 0.01] | |
Total events:	0 | 0 | | | | |

Test for overall effect: Z = 0.00 (P = 1.00)
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.00, df = 1 (P = 1.00); I² = 0%

Total (Walda)	1035 | | 726 | 100.0% | 0.00 [-0.00 , 0.01] | |
Total events:	4 | 1 | | | | |
Test for overall effect: Z = 0.60 (P = 0.55) | | | | -100 | -50 | 50	100
Test for subgroup differences: Chi² = 0.08, df = 1 (P = 0.77), I² = 0% | | | Favours PD-1/PD-L1 inhibitors plus NACT | Favours NACT
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.13, df = 3 (P = 0.99); I² = 0%
Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.

Comparison 3. PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy – subgroup analysis by PD-L1 status
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size
3.1 Pathological complete response | 5 | 1410 | Risk Ratio (IV, Random, 95% CI) | 1.26 [1.13, 1.39]
3.1.1 Positive | 5 | 964 | Risk Ratio (IV, Random, 95% CI) | 1.25 [1.11, 1.40]
3.1.2 Negative | 5 | 446 | Risk Ratio (IV, Random, 95% CI) | 1.30 [1.01, 1.67]
3.2 Event-free survival | 2 | | Hazard Ratio (IV, Random, 95% CI) | 0.63 [0.50, 0.79]
3.2.1 Positive | 2 | | Hazard Ratio (IV, Random, 95% CI) | 0.65 [0.50, 0.85]
3.2.2 Negative | 2 | | Hazard Ratio (IV, Random, 95% CI) | 0.55 [0.33, 0.90]
3.3 Overall survival | 1 | | Hazard Ratio (IV, Random, 95% CI) | 0.25 [0.07, 0.91]
3.3.1 Positive | 1 | | Hazard Ratio (IV, Random, 95% CI) | 0.17 [0.04, 0.78]
3.3.2 Negative | 1 | | Hazard Ratio (IV, Random, 95% CI) | 0.66 [0.06, 7.26]

Analysis 3.1. Comparison 3: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant
chemotherapy – subgroup analysis by PD-L1 status, Outcome 1: Pathological complete response

PD-1/PD-L1 inhibitors plus NACT	NACT
Study or Subgroup	Events	Total	Events Total

Weight

Risk Ratio
IV, Random, 95% CI

Risk Ratio
IV, Random, 95% CI

3.1.1 Positive
GeparNuevo	40	69
IMpassion031	53	77
KEYNOTE-522	230	334
NCI 10013	12	16
NeoTRIP	47	79
Subtotal (Walda)	575
Total events:	382
Test for overall effect: Z = 3.81 (P = 0.0001)
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 3.04, df = 4 (P = 0.55); I² =

35
37
90
0
40
202
0%

69
75
164
4
77
389

11.3%
14.2%
43.8%
0.2%
13.5%
83.0%

1.14 [0.84 , 1.55]
1.40 [1.06 , 1.84]
1.25 [1.07 , 1.47]
7.35 [0.52 , 103.55]
1.15 [0.86 , 1.52]
1.25 [1.11 , 1.40]

3.1.2 Negative
GeparNuevo	4	9
IMpassion031	42	88
KEYNOTE-522	29	64
NCI 10013	6	19
NeoTRIP	20	59
Subtotal (Walda)	239
Total events:	101
Test for overall effect: Z = 2.04 (P = 0.04)
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 2.64, df = 4 (P = 0.62); I² =

2
32
10
1
23
68
0%

11
93
33
5
65
207

0.5%
8.5%
3.1%
0.3%
4.6%
17.0%

2.44 [0.57 , 10.43]
1.39 [0.97 , 1.98]
1.50 [0.83 , 2.68]
1.58 [0.24 , 10.28]
0.96 [0.59 , 1.56]
1.30 [1.01 , 1.67]

Total (Walda)	814
Total events:	483

270

596

100.0%

1.26 [1.13 , 1.39]

Test for overall effect: Z = 4.31 (P < 0.0001) Test for subgroup differences: Chi² = 0.08, df = 1 (P = 0.77), I² = 0% Heterogeneity: Tau² (DLb) = 0.00; Chi² = 5.76, df = 9 (P = 0.76); I² = | 0% | | | 0.01	0.1 Favours NACT | 10	100 Favours PD-1/PD-L1 inhibitors plus NACT

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.
Analysis 3.2. Comparison 3: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs
neoadjuvant chemotherapy – subgroup analysis by PD-L1 status, Outcome 2: Event-free survival
Hazard Ratio	Hazard Ratio
Study or Subgroup log[Hazard Ratio] SE Weight IV, Random, 95% CI	IV, Random, 95% CI

3.2.1		Positive
GeparNuevo	-0.820981	0.426202	7.7%
KEYNOTE-522	-0.385662	0.140792	70.8%
Subtotal (Walda)	78.5%
Test for overall effect: Z = 3.21 (P = 0.001)
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.94, df = 1 (P = 0.33); I² = 0%
3.2.2		Negative
GeparNuevo	-0.223144 0.912684	1.7%

0.44 [0.19 , 1.01]
0.68 [0.52 , 0.90]
0.65 [0.50 , 0.85]
0.80 [0.13 , 4.79]

KEYNOTE-522	-0.634878 0.266166	19.8% | 0.53 [0.31 , 0.89] | |

Subtotal (Walda)	21.5%
Test for overall effect: Z = 2.36 (P = 0.02)
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.19, df = 1 (P = 0.66); I² = 0%

0.55 [0.33 , 0.90]

Total (Walda)	100.0% | 0.63 [0.50 , 0.79] | |
Test for overall effect: Z = 3.93 (P < 0.0001) | 0.01 | 0.1 | 10	100
Test for subgroup differences: Chi² = 0.36, df = 1 (P = 0.55), I² = 0% Heterogeneity: Tau² (DLb) = 0.00; Chi² = 1.49, df = 3 (P = 0.68); I² = 0% | Favours PD-1/PD-L1 inhibitors plus NACT | Favours NACT

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.
Analysis 3.3. Comparison 3: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs
neoadjuvant chemotherapy – subgroup analysis by PD-L1 status, Outcome 3: Overall survival

Hazard Ratio
IV, Random, 95% CI

Hazard Ratio
Study or Subgroup log[Hazard Ratio] SE Weight IV, Random, 95% CI

GeparNuevo	-1.754464 | 0.770858 | 71.6%
Subtotal | | 71.6%
Test for overall effect: Z = 2.28 (P = 0.02) | |
Heterogeneity: Not applicable | |

3.3.1 Positive

0.17 [0.04 , 0.78]
0.17 [0.04 , 0.78]

3.3.2 Negative
GeparNuevo
Subtotal

-0.417032	1.22414	28.4%

28.4%

0.66 [0.06 , 7.26]
0.66 [0.06 , 7.26]

Test for overall effect: Z = 0.34 (P = 0.73)
Heterogeneity: Not applicable

Total (Walda)	100.0%

0.25 [0.07 , 0.91]

Test for overall effect: Z = 2.11 (P = 0.04)
Test for subgroup differences: Chi² = 0.85, df = 1 (P = 0.36), I² = 0%
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.85, df = 1 (P = 0.36); I² = 0%

0.01	0.1	1	10	100
Favours PD-1/PD-L1 inhibitors plus NACT Favours NACT

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.

Comparison 4. PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy – subgroup analysis by age
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size
4.1 Pathological complete response | 1 | 602 | Risk Ratio (IV, Random, 95% CI) | 1.25 [1.07, 1.45]
4.1.1 < 65 years | 1 | 531 | Risk Ratio (IV, Random, 95% CI) | 1.23 [1.05, 1.43]
4.1.2 ≥ 65 years | 1 | 71 | Risk Ratio (IV, Random, 95% CI) | 1.70 [0.90, 3.19]
4.2 Event-free survival | 1 | | Hazard Ratio (IV, Random, 95% CI) | 0.72 [0.46, 1.12]
4.2.1 < 65 years | 1 | | Hazard Ratio (IV, Random, 95% CI) | 0.61 [0.47, 0.80]
4.2.2 ≥ 65 years | 1 | | Hazard Ratio (IV, Random, 95% CI) | 0.99 [0.54, 1.82]

Analysis 4.1. Comparison 4: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs
neoadjuvant chemotherapy – subgroup analysis by age, Outcome 1: Pathological complete response
| PD-1/PD-L1 inhibitors plus NACT	NACT	Risk Ratio	Risk Ratio
Study or Subgroup | Events	Total	Events Total Weight IV, Random, 95% CI	IV, Random, 95% CI

4.1.1 < 65 years |

KEYNOTE-522	235	355	95	176	94.3%	1.23 [1.05 , 1.43]
Subtotal	355	176	94.3%	1.23 [1.05 , 1.43]
Total events:	235	95
Test for overall effect: Z = 2.57 (P = 0.01)
Heterogeneity: Not applicable
4.1.2 ≥ 65 years

KEYNOTE-522	25	46	8	25	5.7%	1.70 [0.90 , 3.19] |

Subtotal	46	25	5.7%	1.70 [0.90 , 3.19]
Total events:	25	8
Test for overall effect: Z = 1.65 (P = 0.10)
Heterogeneity: Not applicable
Total (Walda)	401	201 100.0%	1.25 [1.07 , 1.45]
Total events:	260	103
Test for overall effect: Z = 2.89 (P = 0.004)	_0.01	_0.1
Test for subgroup differences: Chi² = 0.97, df = 1 (P = 0.33), I² = 0%	Favours NACT

1	10	100
Favours PD-1/PD-L1 inhibitors plus NACT

Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.97, df = 1 (P = 0.33); I² = 0%
Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.

Analysis 4.2. Comparison 4: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs
neoadjuvant chemotherapy – subgroup analysis by age, Outcome 2: Event-free survival

Study or Subgroup	log[Hazard Ratio]	SE	Weight

Hazard Ratio
IV, Random, 95% CI

Hazard Ratio
IV, Random, 95% CI

4.2.1 < 65 years | | | |
KEYNOTE-522	-0.494296 0.135686	66.6% | 0.61 [0.47 , 0.80] | | |
Subtotal	66.6% | 0.61 [0.47 , 0.80] | | |
Test for overall effect: Z = 3.64 (P = 0.0003) Heterogeneity: Not applicable | | | |
4.2.2 ≥ 65 years | | | |
KEYNOTE-522	-0.01005	0.30996	33.4% | 0.99 [0.54 , 1.82] | | |
Subtotal	33.4% | 0.99 [0.54 , 1.82] | | |

Test for overall effect: Z = 0.03 (P = 0.97)
Heterogeneity: Not applicable

Total (Walda)	100.0% | 0.72 [0.46 , 1.12] | | |
Test for overall effect: Z = 1.45 (P = 0.15) | 0.01 | 0.1 | 10 | 100
Test for subgroup differences: Chi² = 2.05, df = 1 (P = 0.15), I² = 51.2% | Favours PD-1/PD-L1 inhibitors plus NACT | Favours NACT
Heterogeneity: Tau² (DLb) = 0.06; Chi² = 2.05, df = 1 (P = 0.15); I² = 51%

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.
Comparison 5. PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy – subgroup analysis by ECOG score
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size
5.1 Pathological complete response | 2 | 933 | Risk Ratio (IV, Random, 95% CI) | 1.27 [1.05, 1.54]
5.1.1 ECOG score 0 | 2 | 810 | Risk Ratio (IV, Random, 95% CI) | 1.34 [1.17, 1.53]
5.1.2 ECOG score 1 | 2 | 123 | Risk Ratio (IV, Random, 95% CI) | 1.46 [0.51, 4.18]
5.2 Event-free survival | 1 | | Hazard Ratio (IV, Random, 95% CI) | 0.65 [0.51, 0.83]
5.2.1 ECOG score 0 | 1 | | Hazard Ratio (IV, Random, 95% CI) | 0.63 [0.49, 0.82]
5.2.2 ECOG score 1 | 1 | | Hazard Ratio (IV, Random, 95% CI) | 0.80 [0.43, 1.49]

Analysis 5.1. Comparison 5: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant
chemotherapy – subgroup analysis by ECOG score, Outcome 1: Pathological complete response
| PD-1/PD-L1 inhibitors plus NACT	NACT	Risk Ratio	Risk Ratio
Study or Subgroup | Events	Total	Events Total Weight IV, Random, 95% CI	IV, Random, 95% CI

5.1.1 ECOG score 0 | | | | | | |
IMpassion031	90	156	66 | 153	33.5% | 1.34 [1.07 , 1.68] | | | | |

KEYNOTE-522	215	328	85
Subtotal (Walda)	484
Total events:	305	151
Test for overall effect: Z = 4.16 (P < 0.0001)
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.00, df = 1 (P = 0.99); I² = 0%
5.1.2 ECOG score 1
IMpassion031	5	8	3

173	41.7%
326	75.1%
14	2.8%

1.33 [1.12 , 1.58]
1.34 [1.17 , 1.53]
2.92 [0.94 , 9.10]

KEYNOTE-522	45	73	18 | 28	22.1% | 0.96 [0.69 , 1.33] | | | | |
Subtotal (Walda)	81 | 42	24.9% | 1.46 [0.51 , 4.18] | | | | |

Total events:	50	21
Test for overall effect: Z = 0.70 (P = 0.49)
Heterogeneity: Tau² (DLb) = 0.44; Chi² = 3.39, df = 1 (P = 0.07); I² = 70%

Total (Walda)	565 | 368 100.0% | 1.27 [1.05 , 1.54] | | | | |
Total events:	355	172 | | | | | | |
Test for overall effect: Z = 2.41 (P = 0.02) | | | 0.01 | 0.1 | | 10 | 100
Test for subgroup differences: Chi² = 0.03, df = 1 (P = 0.87), I² = 0% | | | Favours NACT | | Favours PD-1/PD-L1 inhibitors plus NACT
Heterogeneity: Tau² (DLb) = 0.02; Chi² = 5.32, df = 3 (P = 0.15); I² = 44%
Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.

Analysis 5.2. Comparison 5: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs
neoadjuvant chemotherapy – subgroup analysis by ECOG score, Outcome 2: Event-free survival
| Hazard Ratio	Hazard Ratio
Study or Subgroup | log[Hazard Ratio]	SE	Weight IV, Random, 95% CI	IV, Random, 95% CI

5.2.1 ECOG score 0
KEYNOTE-522	-0.462035
Subtotal
Test for overall effect: Z = 3.49 (P = 0.0005)
Heterogeneity: Not applicable

0.132286

85.2%
85.2%

0.63 [0.49 , 0.82]
0.63 [0.49 , 0.82]

5.2.2 ECOG score 1
KEYNOTE-522	-0.223144
Subtotal
Test for overall effect: Z = 0.70 (P = 0.48)
Heterogeneity: Not applicable

0.317033

14.8%
14.8%

0.80 [0.43 , 1.49]
0.80 [0.43 , 1.49]

Total (Walda) | | 100.0% | 0.65 [0.51 , 0.83] | |

Test for overall effect: Z = 3.49 (P = 0.0005)
Test for subgroup differences: Chi² = 0.48, df =

1 (P = 0.49), I²

= 0%

0.01	0.1
Favours PD-1/PD-L1 inhibitors plus NACT

10	100
Favours NACT

Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.48, df = 1 (P = 0.49); I² = 0%

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.

Comparison 6. PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy – sensitivity analysis excluding studies with high risk of bias
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size
6.1 Serious adverse events | 4 | 1955 | Odds Ratio (IV, Random, 95% CI) | 1.86 [1.20, 2.90]

Analysis 6.1. Comparison 6: PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant
chemotherapy – sensitivity analysis excluding studies with high risk of bias, Outcome 1: Serious adverse events

Study or Subgroup

PD-1/PD-L1 inhibitors plus NACT

NACT
Events Total

Weight

Odds Ratio
IV, Random, 95% CI

Odds Ratio
IV, Random, 95% CI

| Events | Total | | | |
GeparNuevo | 30 | 92 | 29	82 | 22.4% | 0.88 [0.47 , 1.66] |
IMpassion031 | 50 | 164 | 30	167 | 26.2% | 2.00 [1.20 , 3.36] |
KEYNOTE-522 | 267 | 783 | 78	389 | 34.8% | 2.06 [1.55 , 2.75] |

NeoTRIP
Total (Walda)
Total events:
Test for overall effect: Z

25
372
= 2.76 (P = 0.006)

138
1177

8	140
778
145

16.6%
100.0%

3.65 [1.58 , 8.41]
1.86 [1.20 , 2.90]
0.01	0.1	1	10	100
Favours PD-1/PD-L1 inhibitors plus NACT	Favours NACT

Heterogeneity: Tau² (DLb) = 0.12; Chi² = 8.39, df = 3 (P = 0.04); I² = 64%
Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.

Comparison 7. PD-1 or PD-L1 inhibitors plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy – sensitivity analysis excluding a study that did not report EFS definition
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size
7.1 Event-free survival | 3 | | Hazard Ratio (IV, Random, 95% CI) | 0.64 [0.52, 0.80]

Analysis 7.1. Comparison 7: PD-1 or PD-L1 inhibitors plus neoadjuvant
chemotherapy vs neoadjuvant chemotherapy – sensitivity analysis excluding
a study that did not report EFS definition, Outcome 1: Event-free survival

Study or Subgroup

log[Hazard Ratio]

SE

Weight

Hazard Ratio
IV, Random, 95% CI

Hazard Ratio
IV, Random, 95% CI

GeparNuevo | -0.733969 | 0.356297 | 9.6% | 0.48 [0.24 , 0.96] | |
IMpassion031 | -0.274437 | 0.326775 | 11.4% | 0.76 [0.40 , 1.44] | |
KEYNOTE-522 | -0.430783 | 0.124241 | 79.0% | 0.65 [0.51 , 0.83] | |
Total (Walda) | | | 100.0% | 0.64 [0.52 , 0.80] | |
Test for overall effect: Z | = 4.00 (P < 0.0001) | | | 0.01 | 0.1 | 10	100
| | | Favours PD-1/PD-L1 inhibitors plus NACT | Favours NACT
Heterogeneity: Tau² (DLb) = 0.00; Chi² = 0.94, df = 2 (P = 0.62); I² = 0%

Footnotes
aCI calculated by Wald-type method.
bTau² calculated by DerSimonian and Laird method.
Comparison 8. PD-1 or PD-L1 inhibitors plus adjuvant chemotherapy vs adjuvant chemotherapy
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size
8.1 Event-free survival | 1 | | Hazard Ratio (IV, Random, 95% CI) | 1.11 [0.87, 1.42]
8.2 Overall survival | 1 | | Hazard Ratio (IV, Random, 95% CI) | 1.23 [0.87, 1.73]
8.3 Health-related quality of life | 1 | 2168 | Mean Difference (IV, Random, 95% CI) | -1.02 [-2.71, 0.67]
8.4 Any adverse events | 1 | 2177 | Odds Ratio (IV, Random, 95% CI) | 3.38 [0.93, 12.33]
8.5 Serious adverse events | 1 | 2177 | Odds Ratio (IV, Random, 95% CI) | 1.81 [1.47, 2.24]
8.6 Treatment-related deaths | 1 | 2177 | Risk Difference (IV, Random, 95% CI) | -0.00 [-0.00, 0.00]

Analysis 8.1. Comparison 8: PD-1 or PD-L1 inhibitors plus adjuvant
chemotherapy vs adjuvant chemotherapy, Outcome 1: Event-free survival
| Hazard Ratio	Hazard Ratio
Study or Subgroup	log[Hazard Ratio] | SE	Weight IV, Random, 95% CI	IV, Random, 95% CI
ALEXANDRA/IMpassion030	0.10436 | 0.124982 100.0%	1.11 [0.87 , 1.42]
Total | 100.0%	1.11 [0.87 , 1.42]

Test for overall effect: Z = 0.84 (P = 0.40)

0.01	0.1	1	10	100
Favours PD-1/PD-L1 inhibitors plus ACT	Favours ACT

Heterogeneity: Not applicable

Analysis 8.2. Comparison 8: PD-1 or PD-L1 inhibitors plus adjuvant
chemotherapy vs adjuvant chemotherapy, Outcome 2: Overall survival

Study or Subgroup

log[Hazard Ratio]

SE

Weight

Hazard Ratio
IV, Random, 95% CI

Hazard Ratio
IV, Random, 95% CI

ALEXANDRA/IMpassion030 | 0.207014 | 0.175356 | 100.0% | 1.23 [0.87 , 1.73] | |
Total | | | 100.0% | 1.23 [0.87 , 1.73] | |
Test for overall effect: Z = 1.18 (P | = 0.24) | | | 0.01	0.1 Favours PD-1/PD-L1 inhibitors plus ACT | 10	100 Favours ACT
Heterogeneity: Not applicable

Analysis 8.3. Comparison 8: PD-1 or PD-L1 inhibitors plus adjuvant chemotherapy
vs adjuvant chemotherapy, Outcome 3: Health-related quality of life

PD-1/PD-L1 inhibitors plus ACT

ACT

Weight

Mean Difference
IV, Random, 95% CI

Mean Difference
IV, Random, 95% CI

Study or Subgroup	Mean | SD	Total	Mean | SD | Total | | |
ALEXANDRA/IMpassion030	0.19 | 19.84	1087	1.21 | 20.42 | 1081 | 100.0% | -1.02 [-2.71 , 0.67] | | |
Total | 1087 | | 1081 | 100.0% | -1.02 [-2.71 , 0.67] | | |
Test for overall effect: Z = 1.18 (P = 0.24) | | | | | | -100	-50 Favours ACT | 0	50	100 Favours PD-1/PD-L1 inhibitors plus ACT
Heterogeneity: Not applicable

Analysis 8.4. Comparison 8: PD-1 or PD-L1 inhibitors plus adjuvant
chemotherapy vs adjuvant chemotherapy, Outcome 4: Any adverse events

Study or Subgroup

PD-1/PD-L1 inhibitors plus ACT

ACT

Weight

Odds Ratio
IV, Random, 95% CI

Odds Ratio
IV, Random, 95% CI

| Events | Total | Events | Total | | |
ALEXANDRA/IMpassion030 | 1090 | 1093 | 1074 | 1084 | 100.0% | 3.38 [0.93 , 12.33] | | |
Total | | 1093 | | 1084 | 100.0% | 3.38 [0.93 , 12.33] | | |
Total events: | 1090 | | 1074 | | | | | |
Test for overall effect: Z = 1.85 (P | = 0.06) | | | | | 0.01 | 0.1 | 10 | 100
Favours PD-1/PD-L1 inhibitors plus ACT Favours ACT
Heterogeneity: Not applicable
Analysis 8.5. Comparison 8: PD-1 or PD-L1 inhibitors plus adjuvant
chemotherapy vs adjuvant chemotherapy, Outcome 5: Serious adverse events

Study or Subgroup

PD-1/PD-L1 inhibitors plus ACT

ACT

Weight

Odds Ratio
IV, Random, 95% CI

Odds Ratio
IV, Random, 95% CI

| Events | Total | Events | Total | | |
ALEXANDRA/IMpassion030 | 280 | 1093 | 173 | 1084 | 100.0% | 1.81 [1.47 , 2.24] |
Total | | 1093 | | 1084 | 100.0% | 1.81 [1.47 , 2.24] |
Total events: | 280 | | 173 | | | |
Test for overall effect: Z = 5.51 (P | < 0.00001) | | | | | 0.01 | 0.1	1	10	100
Favours PD-1/PD-L1 inhibitors plus ACT Favours ACT
Heterogeneity: Not applicable

Analysis 8.6. Comparison 8: PD-1 or PD-L1 inhibitors plus adjuvant
chemotherapy vs adjuvant chemotherapy, Outcome 6: Treatment-related deaths

Study or Subgroup

PD-1/PD-L1 inhibitors plus ACT Events	Total

ACT
Events Total

Weight

Risk Difference
IV, Random, 95% CI

Risk Difference
IV, Random, 95% CI

ALEXANDRA/IMpassion030 | | 0 | 1093 | 1	1084 | 100.0% | -0.00 [-0.00 , 0.00] | |
Total Total events: | | 0 | 1093 | 1084 1 | 100.0% | -0.00 [-0.00 , 0.00] | |
Test for overall effect: Z = 0.71 (P Heterogeneity: Not applicable | = 0.48) | | | | | -100 Favours PD-1/PD-L1 inhibitors | -50 plus ACT | 50	100 Favours ACT

A P P E N D I C E S
Appendix 1. CENTRAL search strategy
#		1 MeSH descriptor: [Breast Neoplasms] explode all trees
#		2 triple negative breast near neoplasm*
#		3 triple negative breast near carcinoma*
#		4 triple negative breast near cancer*
#		5 triple negative breast near tumour*
#		6 triple negative breast near tumor*
#		7 #1 or #2 or #3 or #4 or #5 or #6
#		8 MeSH descriptor: [Immunotherapy] explode all trees
#		9 MeSH descriptor: [Immune Checkpoint Inhibitors] explode all trees
#		10 immunotherap*
#		11 immune checkpoint inhibitor*
#		12 PD-1 Inhibitor* or Programmed Cell Death Protein 1 Inhibitor*
#		13 PD-L1 Inhibitor* or Programmed Death-Ligand 1 Inhibitor*
#		14 MeSH descriptor: [Nivolumab] explode all trees
#		15 nivolumab or pembrolizumab or lambrolizumab or pidilizumab or tislelizumab or atezolizumab or avelumab or durvalumab or cemiplimab or dostarlimab or spartalizumab or toripalimab
#		16 #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15
#		17 MeSH descriptor: [Antineoplastic Agents] explode all trees
#		18 MeSH descriptor: [Antineoplastic Combined Chemotherapy Protocols] explode all trees
#		19 MeSH descriptor: [Antineoplastic Agents, Immunological] explode all trees
#		20 MeSH descriptor: [Neoadjuvant Therapy] explode all trees
#		21 MeSH descriptor: [Chemotherapy, Adjuvant] explode all trees
#		22 chemoimmunotherap*
#		23 #17 or #18 or #19 or #20 or #21 or #22
#		24 #16 and #23
#		25 #7 and #24 in Trials

Appendix 2. MEDLINE (via OvidSP) search strategy
# | Searches
1 | exp Breast Neoplasms/
2 | exp Triple Negative Breast Neoplasms/
3 | Triple Negative Breast cancer$.tw.
4 | Triple Negative Breast neoplasm$.tw.
5 | Triple Negative Breast carcinoma$.tw.
6 | Triple Negative Breast tumo?r$.tw.
7 | or/1-6
8 | exp Immunotherapy/
9 | immunotherap*.tw.
10 | exp Immune Checkpoint Inhibitors/
11 | immune checkpoint inhibitor*.tw.
12 | PD-1 Inhibitor*.mp.
13 | PD-L1 Inhibitor*.mp.
14 | Programmed Cell Death Protein 1 Inhibitor*.mp.
15 | Programmed Death-Ligand 1 Inhibitor*.mp.
16 | exp Nivolumab/
17 | (nivolumab or Opdivo or MDX-1106 or MDX 1106 or ONO 4538 or ONO-4538).mp.
18 | (pembrolizumab or MK-3475 or lambrolizumab or Keytruda or MK 3475 or Sch 900475 or SCH-900475).mp.
19 | (pidilizumab or CT011 or CT-011).mp.
20 | (tislelizumab or BGB-A317 or BGB A317).mp.
21 | (atezolizumab or Tecentriq or MPDL 3280A or MPDL-3280A or MPDL3280A or RG 7446 or RG-7446).mp.
22 | (avelumab or Bavencio or MSB-0010682 or MSB0010682 or MSB0010718C).mp.
23 | (durvalumab or Imfinzi or MEDI 4736 or MEDI4736).mp.
24 | (cemiplimab or REGN 2810 or REGN-2810 or REGN2810 or Libtayo).mp.
25 | (dostarlimab or TSR-042 or "TSR 042" or WBP-285 or WBP 285 or Jemperli).mp.

(Continued)
26

(Spartalizumab or PDR001 or PDR-001 or NVP-LZV184 or NVP LZV184).mp.

27 | (Toripalimab or JS001 or TAB001).mp.
28 | or/8-27
29 | chemoimmunotherap*.tw.
30 | exp Antineoplastic Combined Chemotherapy Protocols/
31 | exp Neoadjuvant Therapy/
32 | exp Antineoplastic Agents/
33 | exp Chemotherapy, Adjuvant/
34 | exp Antineoplastic Agents, Immunological/
35 | or/29-34
36 | 28 and 35
37 | 7 and 36
38 | animals/ not humans/
39 | 37 not 38
40 | randomized controlled trial.pt.
41 | controlled clinical trial.pt.
42 | randomized.ab.
43 | placebo.ab.
44 | Clinical Trials as Topic/
45 | randomly.ab.
46 | trial.ti.
47 | (crossover or cross-over).tw.
48 | Pragmatic Clinical Trials as Topic/
49 | pragmatic clinical trial.pt.
50 | or/40-49
51 | 39 and 50
52 | limit 51 to yr="2005 -Current"

Appendix 3. Embase (via OvidSP) search strategy
# | Searches
1 | exp breast cancer/
2 | exp triple negative breast cancer/
3 | Triple Negative Breast cancer$.tw.
4 | Triple Negative Breast neoplasm$.tw.
5 | Triple Negative Breast carcinoma$.tw.
6 | Triple Negative Breast tumo?r$.tw.
7 | or/1-6
8 | exp immunotherapy/
9 | exp cancer immunotherapy/
10 | immunotherap*.tw.
11 | exp immune checkpoint inhibitor/
12 | immune checkpoint inhibitor*.tw.
13 | PD-1 Inhibitor*.mp.
14 | PD-L1 Inhibitor*.mp.
15 | Programmed Cell Death Protein 1 Inhibitor*.mp.
16 | Programmed Death-Ligand 1 Inhibitor*.mp.
17 | exp nivolumab/
18 | (nivolumab or Opdivo or MDX-1106 or MDX 1106 or ONO 4538 or ONO-4538).mp.
19 | exp pembrolizumab/
20 | (pembrolizumab or MK-3475 or lambrolizumab or Keytruda or MK 3475 or Sch 900475 or SCH-900475).mp.
21 | exp pidilizumab/
22 | (pidilizumab or CT011 or CT-011).mp.
23 | exp tislelizumab/
24 | (tislelizumab or BGB-A317 or BGB A317).mp.
25 | exp atezolizumab/

(Continued) |
26 | (atezolizumab or Tecentriq or MPDL 3280A or MPDL-3280A or MPDL3280A or RG 7446 or RG-7446).mp.
27 | exp avelumab/
28 | (avelumab or Bavencio or MSB-0010682 or MSB0010682 or MSB0010718C).mp.
29 | exp durvalumab/
30 | (durvalumab or Imfinzi or MEDI 4736 or MEDI4736).mp.
31 | exp cemiplimab/
32 | (cemiplimab or REGN 2810 or REGN-2810 or REGN2810 or Libtayo).mp.
33 | exp dostarlimab/
34 | (dostarlimab or TSR-042 or "TSR 042" or WBP-285 or WBP 285 or Jemperli).mp.
35 | exp spartalizumab/
36 | (Spartalizumab or PDR001 or PDR-001 or NVP-LZV184 or NVP LZV184).mp.
37 | exp toripalimab/
38 | (Toripalimab or JS001 or TAB001).mp.
39 | or/8-38
40 | exp antineoplastic agent/
41 | exp neoadjuvant therapy/
42 | exp adjuvant chemotherapy/
43 | exp immunological antineoplastic agent/
44 | chemoimmunotherap*.tw.
45 | or/40-44
46 | 39 and 45
47 | 7 and 46
48 | Randomized controlled trial/
49 | Controlled clinical study/
50 | Random$.ti,ab.
51 | randomization/
52 | intermethod comparison/
53 | placebo.ti,ab.

(Continued)
54

(compare or compared or comparison).ti.

55 | (open adj label).ti,ab.
56 | ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab.
57 | double blind procedure/
58 | parallel group$1.ti,ab.
59 | (crossover or cross over).ti,ab.
60 | ((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or pa- tient$1 or subject$1 or participant$1)).ti,ab.
61 | (assigned or allocated).ti,ab.
62 | (controlled adj7 (study or design or trial)).ti,ab.
63 | (volunteer or volunteers).ti,ab.
64 | trial.ti.
65 | or/48-64
66 | 47 and 65
67 | limit 66 to (human and embase and yr="2005 -Current")
68 | remove duplicates from 67

Appendix 4. WHO ICTRP search strategy
Basic searches:
1.		Triple negative breast cancer AND immune checkpoint inhibitor*
2.		Triple negative breast cancer AND immunotherap*
Advanced searches:
1.		Condition:triple negative breast cancer OR triple negative breast neoplasm
Intervention: immune checkpoint inhibitor*
Recruitment status: All
2.		Condition: triple negative breast cancer OR triple negative breast neoplasm
Intervention: immunotherap*
Recruitment status:All
3.		Condition: triple negative breast cancer OR triple negative breast neoplasm
Intervention: PD-1 inhibitor* OR PD-L1 inhibitor* OR Programmed Cell Death Protein 1 inhibitor* OR Programmed Death-Ligand 1 inhibitor* OR nivolumab OR pembrolizumab OR lambrolizumab OR pidilizumab OR tislelizumab OR atezolizumab OR avelumab OR durvalumab OR cemiplimab OR dostarlimab OR Spartalizumab OR Toripalimab
Recruitment status: All
4.		Condition: triple negative breast cancer OR triple negative breast neoplasm
Intervention: Opdivo OR MDX-1106 OR ONO-4538 OR MK-3475 OR Keytruda OR SCH-900475 OR CT-011 OR BGB-A317 OR MPDL-3280A OR RG-7446 OR Bavencio OR MSB-0010682 OR MSB0010718C OR Imfinzi OR MEDI4736 OR REGN-2810 OR Libtayo OR TSR-042 OR WBP-285 OR Jemperli OR PDR-001 OR NVP-LZV184 OR JS001 OR TAB001
Recruitment status: All
Appendix 5. ClinicalTrials.gov search strategy
Basic searches:
1.		Condition or disease: Triple negative breast cancer
Other terms: immune checkpoint inhibitor OR immune checkpoint inhibitors
2.		Condition or disease: Triple negative breast cancer
Other terms: immunotherapy OR immunotherapies
Advanced searches:
1.		Condition or disease: Triple negative breast cancer OR triple negative breast neoplasm
Intervention/treatment: PD-1 inhibitor OR PD-1 inhibitors OR PD-L1 inhibitor OR PD-L1 inhibitors OR Programmed Cell Death Protein 1 inhibitor OR Programmed Cell Death Protein 1 inhibitors OR Programmed Death-Ligand 1 inhibitor OR Programmed Death-Ligand 1 inhibitors
Study type: All studies
2.		Condition or disease: Triple negative breast cancer OR triple negative breast neoplasm
Intervention/treatment: nivolumab OR pembrolizumab OR lambrolizumab OR pidilizumab OR tislelizumab OR atezolizumab OR avelumab OR durvalumab OR cemiplimab OR dostarlimab OR Spartalizumab OR Toripalimab
Study type: All studies
3.		Condition or disease: Triple negative breast cancer OR triple negative breast neoplasm
Intervention/treatment: Opdivo OR MDX-1106 OR ONO-4538 OR MK-3475 OR Keytruda OR SCH-900475 OR CT-011 OR BGB-A317 OR MPDL-3280A OR RG-7446 OR Bavencio OR MSB-0010682 OR MSB0010718C
Study type: All studies
4.		Condition or disease: Triple negative breast cancer OR triple negative breast neoplasm
Intervention/treatment: Imfinzi OR MEDI4736 OR REGN-2810 OR Libtayo OR TSR-042 OR WBP-285 OR Jemperli OR PDR-001 OR NVP-LZV184 OR JS001 OR TAB001
Study type: All studies
H I S T O R Y
Protocol first published: Issue 9, 2022
C O N T R I B U T I O N S O F A U T H O R S
Drafting the protocol: YG and JT
Study selection: YG, ML, LL
Data extraction: YG, ML, LL
Entering data into RevMan: YG, ML
Performing the analysis: YG, LL, JZ
Interpreting the analysis: YG, ML, LL, JZ, FS, JT
Drafting the final review: YG, JT
Disagreement resolution: JT
Updating the review: YG, ML, LL, JZ, FS, JT
D E C L A R A T I O N S O F I N T E R E S T
YG: none known
ML: none known
LL: none known
JZ: none known
FS: none known
JT: none known
S O U R C E S O F S U P P O R T
Internal sources
•		Evidence-Based Medicine Center, Lanzhou University, China
Methodology support
External sources
•		Qilu Young Scholar Program (202499000161), China
The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
We updated the name of the primary outcome to event-free survival rather than disease-free survival (as published in the protocol). This is because event-free survival better reflects the definition that was used.
We planned to estimate pooled RRs for dichotomous outcomes of adverse events, but due to the high event rates any adverse events and serious adverse events, we estimated the pooled OR instead.
As the duration of interventions was similar across eligible trials, we did not perform planned subgroup analyses for the duration of intervention.
Due to lack of data, we were unable to perform sensitivity analyses by excluding studies with unpublished data, with missing data, or with cross-over, cluster-RCT, or quasi-RCT design.

Immune checkpoint inhibitors and chemotherapy versus chemotherapy for early triple-negative breast cancer
(Review)
Copyright © 2026 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.