Efficacy and safety of immune checkpoint inhibitors combined with chemotherapy in the treatment of triple-negative breast cancer: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

CHAI Xiaoke , ZHOU Haicun , YANG Tao , WEI Chongyi , WEI Yun , ZHANG Xu ,  LONG Jianping

Department of Breast Science, Gansu Provincial Maternal and Child Health Hospital (Gansu Provincial Central Hospital), Lanzhou 730050, P. R. China;

Corresponding author：

LONG Jianping, Email: Longjianping@163.com

Keywords：

Chemotherapy; Immune checkpoint inhibitors; Triple-negative breast cancer; Efficacy and safety; Meta-analysis

DOI：

10.7507/1672-2531.202404085

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Objective To systematically review the efficacy and safety of immune checkpoint inhibitors combined with chemotherapy in the treatment of triple-negative breast cancer. Methods The PubMed, Cochrane Library, Embase, Web of Science, CNKI, WanFang Data and VIP databases were searched for randomised controlled trials (RCTs) of immune checkpoint inhibitors combined with chemotherapy versus chemotherapy alone for triple-negative breast cancer from inception to April 1, 2024. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. Meta-analysis was then performed by using RevMan 5.4 software. Results A total of 13 RCTs involving 5 416 patients were included. The results of meta-analysis showed that the pathologic complete response rate (pCR) (OR=2.09, 95%CI 1.37 to 3.19, P<0.01), progression-free survival (PFS) (HR=0.75, 95%CI 0.67 to 0.83, P<0.01) and overall survival (OS) (HR=0.87, 95%CI 0.79 to 0.96, P<0.01) were significantly better than those in the control group. The results of subgroup analysis showed that there were statistically significant differences in PFS (P<0.01) and OS (P=0.02) between PD-L1-positive and PD-L1-negative patients, but there was no statistically significant difference in pCR between PD-L1-positive patients and PD-L1-negative patients (P=0.36). There was a statistically significant difference in pCR between node-positive patients and node-negative patients (P=0.03). There was no statistically significant difference in pCR between patients treated with PD-1 inhibitors and PD-L1 inhibitors (P=0.32); and there was no significant difference in PFS (P=0.19) or OS (P=0.99) between patients treated with PD-1 inhibitors and PD-L1 inhibitors. Compared with those in the control group, the incidences of serious adverse events (RR=1.36, 95%CI 1.09 to 1.70, P<0.01) and immune-related adverse events (RR=2.98, 95%CI 1.66 to 5.35, P<0.01) were higher in the experimental group, and the common immune-related adverse events were hypothyroidism and hyperthyroidism.Conclusion The existing evidence shows that immune checkpoint inhibitors combined with chemotherapy are more effective than chemotherapy alone in the treatment of triple-negative breast cancer, and the combination therapy has a higher incidence of adverse reactions. Due to the limited quantity and quality of the included studies, more high-quality studies are needed to verify the above conclusion.

Citation： CHAI Xiaoke, ZHOU Haicun, YANG Tao, WEI Chongyi, WEI Yun, ZHANG Xu, LONG Jianping. Efficacy and safety of immune checkpoint inhibitors combined with chemotherapy in the treatment of triple-negative breast cancer: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2025, 25(1): 81-87. doi: 10.7507/1672-2531.202404085 Copy

1.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
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3.	Llop-Guevara A, Loibl S, Villacampa G, et al. Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial. Ann Oncol, 2021, 32(12): 1590-1596.
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5.	Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med, 2020, 382(9): 810-821.
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11.	Loibl S, Schneeweiss A, Huober J, et al. Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response. Ann Oncol, 2022, 33(11): 1149-1158.
12.	Gianni L, Huang CS, Egle D, 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. Ann Oncol, 2022, 33(5): 534-543.
13.	Røssevold AH, Andresen NK, Bjerre CA, et al. Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial. Nat Med, 2022, 28(12): 2573-2583.
14.	Ademuyiwa FO, Gao F, Street CR, 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.
15.	Jiang Z, Ouyang Q, Sun T, et al. Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial. Nat Med, 2024, 30(1): 249-256.
16.	Lehmann BD, Abramson VG, Dees EC, et al. Atezolizumab in combination with carboplatin and survival outcomes in patients with metastatic triple-negative breast cancer: the TBCRC 043 phase 2 randomized clinical trial. JAMA Oncol, 2024, 10(2): 193-201.
17.	Syrnioti A, Petousis S, Newman LA, et al. Triple negative breast cancer: molecular subtype-specific immune landscapes with therapeutic implications. Cancers (Basel), 2024, 16(11): 2094.
18.	Dirix LY, Takacs I, Jerusalem G, et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN solid tumor study. Breast Cancer Res Treat, 2018, 167(3): 671-686.
19.	Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol, 2016, 34(21): 2460-2467.
20.	Adams S, Schmid P, Rugo HS, et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase Ⅱ KEYNOTE-086 study. Ann Oncol, 2019, 30(3): 397-404.
21.	Winer EP, Lipatov O, Im SA, et al. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol, 2021, 22(4): 499-511.
22.	Schmid P, Salgado R, Park YH, et al. Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann Oncol, 2020, 31(5): 569-581.
23.	Li JY, Chen YP, Li YQ, et al. Chemotherapeutic and targeted agents can modulate the tumor microenvironment and increase the efficacy of immune checkpoint blockades. Mol Cancer, 2021, 20(1): 27.
24.	Colombo M, Mondini P, Minenza E, et al. BRCA1A novel splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in: a case report. Front Oncol, 2023, 13: 1102184.
25.	Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers, 2020, 6(1): 38.

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2. Topper MJ, Vaz M, Marrone KA, et al. The emerging role of epigenetic therapeutics in immuno-oncology. Nat Rev Clin Oncol, 2020, 17(2): 75-90.
3. Llop-Guevara A, Loibl S, Villacampa G, et al. Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial. Ann Oncol, 2021, 32(12): 1590-1596.
4. Nanda R, Liu MC, Yau C, 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 Oncol, 2020, 6(5): 676-684.
5. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med, 2020, 382(9): 810-821.
6. Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet, 2020, 396(10257): 1090-1100.
7. Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet, 2020, 396(10265): 1817-1828.
8. Emens LA, Adams S, Barrios CH, et al. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Ann Oncol, 2021, 32(8): 983-993.
9. Miles D, Gligorov J, André F, et al. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase Ⅲ trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol, 2021, 32(8): 994-1004.
10. Bachelot T, Filleron T, Bieche I, et al. Durvalumab compared to maintenance chemotherapy in metastatic breast cancer: the randomized phase Ⅱ SAFIR02-BREAST IMMUNO trial. Nat Med, 2021, 27(2): 250-255.
11. Loibl S, Schneeweiss A, Huober J, et al. Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response. Ann Oncol, 2022, 33(11): 1149-1158.
12. Gianni L, Huang CS, Egle D, 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. Ann Oncol, 2022, 33(5): 534-543.
13. Røssevold AH, Andresen NK, Bjerre CA, et al. Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial. Nat Med, 2022, 28(12): 2573-2583.
14. Ademuyiwa FO, Gao F, Street CR, 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.
15. Jiang Z, Ouyang Q, Sun T, et al. Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial. Nat Med, 2024, 30(1): 249-256.
16. Lehmann BD, Abramson VG, Dees EC, et al. Atezolizumab in combination with carboplatin and survival outcomes in patients with metastatic triple-negative breast cancer: the TBCRC 043 phase 2 randomized clinical trial. JAMA Oncol, 2024, 10(2): 193-201.
17. Syrnioti A, Petousis S, Newman LA, et al. Triple negative breast cancer: molecular subtype-specific immune landscapes with therapeutic implications. Cancers (Basel), 2024, 16(11): 2094.
18. Dirix LY, Takacs I, Jerusalem G, et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN solid tumor study. Breast Cancer Res Treat, 2018, 167(3): 671-686.
19. Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol, 2016, 34(21): 2460-2467.
20. Adams S, Schmid P, Rugo HS, et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase Ⅱ KEYNOTE-086 study. Ann Oncol, 2019, 30(3): 397-404.
21. Winer EP, Lipatov O, Im SA, et al. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol, 2021, 22(4): 499-511.
22. Schmid P, Salgado R, Park YH, et al. Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann Oncol, 2020, 31(5): 569-581.
23. Li JY, Chen YP, Li YQ, et al. Chemotherapeutic and targeted agents can modulate the tumor microenvironment and increase the efficacy of immune checkpoint blockades. Mol Cancer, 2021, 20(1): 27.
24. Colombo M, Mondini P, Minenza E, et al. BRCA1A novel splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in: a case report. Front Oncol, 2023, 13: 1102184.
25. Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers, 2020, 6(1): 38.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of immune checkpoint inhibitors combined with chemotherapy in the treatment of triple-negative breast cancer: a meta-analysis

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