Table 3 Current and upcoming clinical trials of immune checkpoint inhibitors in hormone receptor positive breast cancer

Pembrolizumab

NCT02054806

KEYNOTE-028

Rugo

2018

Phase Ib

Heavily Pretreated

Advanced, PD-L1 CPS ≥ 1

25

Pembrolizumab

ORR 12%

NCT03222856

KELLY

Perez-Garcia

2021

Phase II

> First Line

Advanced

44

Eribulin + Pembrolizumab

CBR 56.8% (95% CI 41.0–71.7)

ORR 40.9% (26.3–56.8)

NCT03051659

Tolaney

2020

Phase II

Two or more lines of hormonal therapy; 0–2 lines of chemotherapy

HR+ /HER2- MBC

88

Arm A: Eribulin + Pembrolizumab

Arm B: Eribulin

ORR 27% (95% CI 14.9–42.8) vs 34% (20.5–39.9)

PFS 4.1 (3.5–6.2) vs 4.2 mo (3.7–6.1), HR 0.80 (0.50–1.26)

OS 13.4 (10.4-NE) vs. 12.5 mo (8.6-NE), HR 0.87 (0.48–1.59)

NCT03044730

Shah

2020

Phase II

Median 1 prior therapy

Metastatic

14

Capecitabine + Pembrolizumab

ORR 14%; PFS 5.1 mo; OS not reached

NCT01042379

I-SPY2

Nanda

2020

Phase II

Neoadjuvant

cT2-4d, cN0-3

HR+ /HER2-

40

Arm A: Weekly paclitaxel + Pembrolizumab followed by AC

Arm B: Weekly paclitaxel + placebo followed by AC

pCR 30% (95% CI: 17–43) vs. 13% (CI 7–19)

NCT02395627

Terranova-Barberio

2020

Phase II

Heavily pretreated, Metastatic ER+ , PD-L1 negative

Metastatic

34

Arm A: Tamoxifen + Vorinostat + Pembrolizumab (C1)

Arm B: Tamoxifen + Vorinostat + Pembrolizumab (C2)

ORR 3.7%

CBR 18.5%

Stopped early for lack of efficacy

NCT03725059

KEYNOTE-756

Cardoso

2023

Phase III

Neoadjuvant & adjuvant

T1c-2, cN1-2 or T3-4, cN0-2; grade 3

1278

Arm A: Pembrolizumab + Paclitaxel then Doxorubicin + Cyclophosphamide → Adjuvant Pembrolizuamb + Endocrine Therapy

Arm B: Placebo + Paclitaxel then Doxorubicin + Cyclophosphamide → Adjuvant Placebo + Endocrine Therapy

pCR 24.3% (95% CI: 21.0–27.8) vs. 15.6% (12.8–18.6) (p = .00005)

Stage II disease pCR 25.8% vs 16.7%

Stage III disease pCR 21.6% vs. 13.6%

N positive pCR 25.1% vs. 15.8%

N negative pCR 16.9% vs. 13.1%

PD-L1 + pCR 29.7% vs 19.6%

PD-L1 + , ER +  < 10% pCR 57.6% vs. PD-L1 + , ER > 10% 33.3%

EFS immature

Atezolizumab

NCT03147040

GELATO

Voorwerk

2023

Phase II

First or second line

Metastatic, HER2- Lobular

23 (18 with ER+ disease, 5 with TNBC)

Carboplatin + Atezolizumab

ORR 17%; CBR 26%

4 of 6 patienst with clinical benefit had TNBC

Tremelimumab

Vonderhiede

2010

Phase I

> First line

Metastatic

26

Tremelimumab + Exemestane

Stable disease in 42% at 12 weeks

Santa Maria

2018

Pilot study

> First line

Metastatic

11

Tremelimumab + Durvalumab

ORR 0%

Durvalumab

NCT02811497

METADUR

Taylor

2020

Phase II

> First line ER+ breast cancer

9

Arm A: Azacitazine + Durvalumab

Arm B: Azacitazine + Durvalumab + vitamin C

no response

NCT02734004

MEDIOLA

Domchek

2020

Phase I/II

> Third line

Metastatic

34

Olaparib + Durvalumab

Tolerable Safety

DCR at 12 weeks 80% (90% CI: 64.3–90.9)

NCT01042379

I-SPY2

Pusztai

2021

Phase II

Neoadjuvant

Stage II-III HR+ /HER2-; MammaPrint high-risk

65

Arm A: Paclitaxel + Durvalumab + Olaparib

Arm B: Paclitaxel

pCR 28% (95% CI 18–38) vs. 14% (9–19);

MammaPrint MP1 pCR 9% (0–18) vs. 10% (5–18)

MammaPrint MP2 pCR 64% (47—80) vs. 22% (13—32)

NCT03875573

Neo-CheckRay

De Caluwe

2024

Phase II

Neoadjuvant

Luminal B, Mammaprint High-Risk

135

Arm A: AC + paclitaxel followed by preoperative radiation

Arm A: AC + paclitaxel + durvalumab followed by preoperative radiation

Arm C: AC + paclitaxel + durvalumab + oleclumab followed by preoperative radiation

pCR 17.8% (95% CI 6.6–28.9) vs 31.8% (18.1–45.6) vs 35.6% (21.6–49.5)

Nivolumab

NCT04659551

GIADA

Dieci

2021

Phase II

Neoadjuvant

Stage II-IIIA, HR+ , HER2-

43

EC followed by Nivolumab + Troptorelin + Exemestane

pCR 16.3% (95% CI: 7.4—34.9)

PAM50 basal pCR 50% vs. Luminal A pCR 9% vs. Luminal B 8% (p = 0.017)

WJOG9917B

NEWBEAT

Ozaki

2022

Phase II

First line

Metastatic HR+ /HER2-

17

Bevacizumab + Nivolumab + Paclitaxel

ORR 74%

PFS 16.1 months

NCT04109066

CheckMate 7FL

Loi

2023

Phase III

Neoadjuvant

Stage T1c-2, N1-2 or T3-4, N0-2

521

Arm A: Nivolumab + Paclitaxel then Doxorubicin + Cyclophosphamide → Adjuvant Endocrine Therapy

Arm B: Placebo + Paclitaxel then Doxorubicin + Cyclophosphamide → Adjuvant Endocrine Therapy

pCR 24.5% (95% CI 19.4–30.2) vs. 13.8% (9.8–13.7), Difference 10.5 (4.0–16.9)

PD-L1 + : pCR 44.3% (33.7–55.3) vs. 20.2% (12.3–30.4), Difference 24.1 (10.7–37.5)

PD-L1-: pCR 14.2% vs. 10.7%

Avelumab

NCT03147287

PACE

Mayer

2024

Phase II

> First line ER+ breast cancer

Metastatic

220

Arm A: Fulvestrant

Arm B: Fulvestrant + Palbociclib

Arm C: Fulvestrant + Palbociclib + Avelumab

PFS Arm A vs Arm B: 4.8 (90% CI 2.1–8.2) vs. 4.6 mo (3.6–5.9), HR 1.11 (0.79–1.55)

PFS Arm A vs Arm C: 4.8 (2.1–8.2) vs 8.1 mo (3.2–10.7), HR 0.75 (0.50–1.12)

ORR Arm A 7.3% (1.5–13.0), Arm B 9.0 (4.5–13.5), Arm C 13.0 (5.4–20.5)

CBR Arm A 29.1 (19.0–39.2), Arm B 32.4 (25.1–39.7), Arm C 35.2 (24.5–45.9)

Combination with CDK4/6 inhibitors

WJOG11418B

NEWFLAME

Masuda

2022

Phase II

First or second line

Metastatic

17

Cohort 1: Nivolumab + Abemaciclib + Fulvestrant

Cohort 2: Nivolumab + Abemaciclib + Letrozole

ORR 54.5% (95% CI 28.0–78.7) vs. 40.0% (11.7–76.9)

Safety: Grade ≥ 3 AE: 92% vs. 100% (neutropenia, hepatotoxicity, ILD)

Early termination for safety

NCT04075604

CheckMate 7A8

Jerusalem

2022

Phase Ib/II

Neoadjuvant

T ≥ 2 cm, ER+ /HER2-

21

Cohort 1: Nivolumab + Palbociclib + Anastrazole

43% treatment discontinuation due to AE (hepatotoxicity, neuropenia, rash, ILD)

Early termination for safety

NCT02779751

Rugo

2022

Phase Ib

Any

Metastatic

28

Cohort 1: Abemaciclib + Pembrolizumab + Anastrazole

Cohort 2: Abemaciclib + Pembrolizumab

ORR 23.1% (95% CI 9.0–43.7) vs. 28.6% (13.2–48.7)

DCR 84.6% (65.1–95.6) vs. 82.1% (63.1–93.9)

Safety: High rates of grade 3 neutropenia, hepatotoxicity, and diarrhea. 2 grade 5 events in cohort 1

LAG-3

NCT02614833

AIPAC

Wildiers

2024

Phase IIb

HR+ , HER2- MBC

Metastatic, ET-resistant

226

Arm A: Paclitaxel + Eftilagimod Alpha

Arm B: Paclitaxel + Placebo

PFS 7.3 (95% CI 6.6–7.5) vs. 7.3 mo (5.5–7.5)

OS 20.4 (14.3–25.1) vs. 17.5 mo (12.9–21.8), HR 0.88 (0.64–1.19)

Age < 65, OS 22.3 mo (15.3–29.6) vs 14.8 (10.9–18.5), HR 0.66 (0.45–0.97)

Selected Upcoming Clinical Trials

NCT06058377

SWOG2206

Phase III

Neoadjuvant

Stage II/III ER+ /HER2-, MP2/High-2

3680

Arm A: Durvalumab plus AC/T—→ Adjuvant ET

Arm B: ACT → Adjuvant ET

pCR

iDFS

NCT05747794

AIPAC 3

Phase III

First line

Metastatic, endocrine-resistant HR+ /HER2- or TNBC

771

Arm A: Paclitaxel + Eftilagimod Alpha

Arm B: Paclitaxel + Placebo

OS

NCT05159778

Phase I/II

Prior CDK4/6, < 2 chemotherapies, no prior ICI

Metastatic, ET-resistant

47

Odetiglucan + Pembrolizumab

ORR

NCT04895358

KEYNOTE-B49

Phase III

Previously treated

Advanced, PD-L1+ 

800

Arm A: Pembrolizumab + Chemotherapy

Arm B: Placebo + Chemotherapy

PFS in patients with CPS ≥ 10