Objective  To systematically evaluate the efficacy and safety of trastuzumab deruxtecan (T-Dxd) in the treatment of breast cancer.

Methods  PubMed, Cochrane Library, Embase, Web of Science, SinoMed, CNKI, WanFang Data, and VIP  databases were electronically searched to collect randomized controlled trials (RCTs) of T-Dxd (test group) versus chemotherapeutic agents or other antineoplastic agents (control group) from inception to February 15, 2024. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias in the included studies. Meta-analysis was performed by using RevMan 5.3.1 software.

Results  A total of 3 RCTs involving 1 689 patients were included. The results of the Meta-analysis indicated that the progression-free survival (PFS) (HR=0.37, 95%CI 0.27 to 0.51, P﹤0.001), overall survival (OS) (HR=0.63, 95%CI 0.53 to 0.75, P﹤0.001), and objective response rate (ORR) (RR=2.52, 95%CI 2.21 to 2.88, P﹤0.001) in the test group were significantly superior to or higher than those of the control group. The incidence of drug-related interstitial lung disease (RR=10.82, 95%CI 4.83 to 24.23, P﹤0.001) and reduced ejection fraction (RR=5.05, 95%CI 1.91 to 13.33, P=0.001) was significantly higher in patients in the test group than in the control group. Subgroup analysis showed that hormone receptor-positive and hormone receptor-negativity, brain metastasis, and no brain metastasis patients who received T-Dxd had longer PFS (P﹤0.001). The results of sensitivity analysis showed that the results obtained were more robust when PFS, OS, and ORR were used as indicators.

Conclusion  Current evidence suggests that T-Dxd can prolong PFS and OS and improve ORR in breast cancer than chemotherapeutic agents or other antineoplastic agents, however, it may increase the risk of interstitial lung disease and reduce ejection fraction. Due to the limited quality and quantity of the included studies, more high-quality studies are needed to verify the above conclusion.

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[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660.

2.Sarhangi N, Hajjari S, Heydari SF, et al. Breast cancer in the era of precision medicine[J]. Mol Biol Rep, 2022, 49(10): 10023-10037. DOI: 10.1007/s11033-022-07571-2.

3.Knezevic CE, Clarke W. Cancer chemotherapy: the case for therapeutic drug monitoring[J]. Ther Drug Monit, 2020, 42(1): 6-19. DOI: 10.1097/ftd.0000000000000701.

4.von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer[J]. N Engl J Med, 2017, 377(2): 122-131. DOI: 10.1056/NEJMoa1703643.

5.Drake PM, Rabuka D. Recent developments in ADC technology: preclinical studies signal future clinical trends[J]. BioDrugs, 2017, 31(6): 521-531. DOI: 10.1007/s40259-017-0254-1.

6.夏凡, 张晶晶, 杭永付, 等.抗体药物偶联物相关眼毒性的研究进展[J]. 药物流行病学杂志, 2023, 32(9): 985-990. [Xia F, Zhang JJ, Hang YF, et al. Research progress of drug-induced ocular toxicity of antibody-drug conjugate[J]. Chinese Journal of Pharmacoepidemiology, 2023, 32(9): 985-990.] DOI: 10.19960/j.issn.1005-0698.202309004.

7.范密,罗婷,张羽,等. Claudin 18.2在恶性实体肿瘤中的研究现状与展望[J]. 华西医学, 2023, 38(9): 1428-1434. [Fan M, Luo T, Zhang Y, et al. Research progress and prospect of Claudin 18.2 in malignant tumors[J]. West China Medical Journal, 2023, 38(9): 1428-1434.] DOI: 10.7507/1002-0179.202303157.

8.Andrikopoulou A, Zografos E, Liontos M, et al. Trastuzumab deruxtecan (DS-8201a): the latest research and advances in breast cancer[J]. Clin Breast Cancer, 2021, 21(3): e212-e219. DOI: 10.1016/j.clbc.2020.08.006.

9.Kay C, Martínez-Pérez C, Meehan J, et al. Current trends in the treatment of HR+/HER2+breast cancer[J]. Future Oncol, 2021, 17(13): 1665-1681. DOI: 10.2217/fon-2020-0504.

10.Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies[J]. ESMO Open, 2022, 7(4): 100554. DOI: 10.1016/j.esmoop.2022. 100554.

11.Takahashi S, Bando H, Kinoshita I, et al. Trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2-expressing salivary gland carcinoma: a pooled analysis of two phase I studies[J]. Jpn J Clin Oncol, 2024, DOI: 10.1093/jjco/hyad181.

12.Modi S. Trastuzumab deruxtecan in previously treated HER2-positive metastatic breast cancer: plain language summary of the DESTINY-Breast01 study[J]. Future Oncol, 2021, 17(26): 3415-3423. DOI: 10.2217/fon-2021-0427.

13.Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials[J]. BMJ, 2011, 343: d5928. DOI: 10.1136/bmj.d5928.

14.Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer[J]. N Engl J Med, 2022, 387(1): 9-20. DOI: 10.1056/NEJMoa2203690.

15.Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer[J]. N Engl J Med, 2022, 386(12): 1142-1154. DOI: 10.1056/NEJMoa2115022.

16.André F, Park YH, Kim SB, et al. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, 3 trial[J]. Lancet, 2023, 401(10390): 1773-1785. DOI: 10.1016/S0140-6736(23)00725-0.

17.Kumagai K, Aida T, Tsuchiya Y, et al. Interstitial pneumonitis related to trastuzumab deruxtecan, a human epidermal growth factor receptor 2-targeting Ab-drug conjugate, in monkeys[J]. Cancer Sci, 2020, 111(12): 4636-4645. DOI: 10.1111/cas.14686.

18.Saura C, Modi S, Krop I, et al. Trastuzumab deruxtecan in previously treated patients with HER2-positive metastatic breast cancer: updated survival results from a phase Ⅱ trial (DESTINY-Breast01)[J]. Ann Oncol, 2024, 35(3): 302-307. DOI: 10.1016/j.annonc.2023.12.001.

19.Rugo HS, Bianchini G, Cortés J, et al. Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer[J]. ESMO Open, 2022, 7(4): 100553. DOI: 10.1016/j.esmoop.2022.100553.

20.Cheng Y, Yuan X, Tian Q, et al. Preclinical profiles of SKB264, a novel anti-TROP2 antibody conjugated to topoisomerase inhibitor, demonstrated promising antitumor efficacy compared to IMMU-132[J]. Front Oncol, 2022, 12: 951589. DOI: 10.3389/fonc.2022.951589.

21.Ferraro E, Drago JZ, Modi S. Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions[J]. Breast Cancer Res, 2021, 23(1): 100554. DOI: 10.1186/s13058-021-01459-y.

22.Chen J, Long JB, Hurria A, et al. Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer[J]. J Am Coll Cardiol, 2012, 60(24): 2504-2512. DOI: 10.1016/j.jacc.2012.07.068.

23.Soares LR, Vilbert M, Rosa VDL, et al. Incidence of interstitial lung disease and cardiotoxicity with trastuzumab deruxtecan in breast cancer patients: a systematic review and single-arm meta-analysis[J]. ESMO Open, 2023, 8(4): 101613. DOI: 10.1016/j.esmoop.2023.101613.

24.Tamura K, Tsurutani J, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study[J]. Lancet Oncol, 2019, 20(6): 816-826. DOI: 10.1016/s1470-2045(19)30097-x.

25.Hackshaw MD, Danysh HE, Singh J, et al. Incidence of pneumonitis/interstitial lung disease induced by HER2-targeting therapy for HER2-positive metastatic breast cancer[J]. Breast Cancer Res Treat, 2020, 183(1): 23-39. DOI: 10.1007/s10549-020-05754-8.

26.王少霞, 陈娇娇, 黄瑞芹, 等. 基于openFDA对曲妥珠单抗和帕妥珠单抗不良反应的比较分析[J]. 药物流行病学杂志, 2022, 31(6): 377-381. [Wang SX, Chen JJ, Huang RQ, et al. Comparative analysis of adverse drug reactions of trastuzumab and pertuzumab based on OpenFDA[J]. Chinese Journal of Pharmacoepidemiology, 2022, 31(6): 377-381.] DOI: 10.19960/j.cnki.issn1005-0698.2022.06.003.

27.Kurokawa YK, Shang MR, Yin RT, et al. Modeling trastuzumab-related cardiotoxicity in vitro using human stem cell-derived cardiomyocytes[J]. Toxicol Lett, 2018, 285: 74-80. DOI: 10.1016/j.toxlet.2018.01.001.

28.Dempsey N, Rosenthal A, Dabas N, et al. Trastuzumab-induced cardiotoxicity: a review of clinical risk factors, pharmacologic prevention, and cardiotoxicity of other HER2-directed therapies[J]. Breast Cancer Research and Treatment, 2021, 188(1): 21-36. DOI: 10.1007/s10549-021-06280-x.

29.Mullard A. Maturing antibody-drug conjugate pipeline hits 30[J]. Nat Rev Drug Discov, 2013, 12(5): 329-332. DOI: 10.1038/nrd4009.

30.Khoury R, Saleh K, Khalife N, et al. Mechanisms of resistance to antibody-drug conjugates[J]. Int J Mol Sci, 2023, 24(11): 9674. DOI: 10.3390/ijms24119674.

31.Su Z, Xiao D, Xie F, et al. Antibody-drug conjugates: Recent advances in linker chemistry[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 3889-3907. DOI: 10.1016/j.apsb.2021.03.042.