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Antibody–drug conjugates (ADCs) are a new class of anticancer agents that combine cytotoxic agents attached by a linker to a monoclonal antibody. These engineered drugs can selectively deliver a cytotoxic payload to targeted cancer cells and the local microenvironment (bystander effect), thereby increasing activity and reducing off-target toxicity. The association of ADCs with other anti-cancer therapies is therefore promising.
Trastuzumab-emtansine was the first approved ADC in breast cancer (BC), specifically for the management of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. New ADCs are in development in BC. Some have shown meaningful clinical benefit and have been recently approved, such as trastuzumab deruxtecan in HER2-positive trastuzumab emtansine (T-DM1) pretreated BC and Trop-2 guided sacituzumab govitecan in triple-negative BC. Trastuzumab deruxtecan also has potential clinical activity in HER2-low BC thanks to a bystander effect. In this article, we review the ADCs under development in advanced BC.
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2- Chau CH, Steeg PS, Figg WD. Antibody – drug conjugates for cancer. Lancet 2019; 394:793 – 804.
3- Hamblett KJ. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res 2004; 10:7063–7070.
4- Lu J, Jiang F, Lu A, Zhang G. Linkers having a crucial role in antibody–drug conjugates. Int J Mol Sci 2016; 17:561.
5- Junttila TT, Li G, Parsons K, et al. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat 2011; 128: 347–356.
6- Ogitani Y, Hagihara K, Oitate M, et al. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody–drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci 2016; 107: 1039–1046.
7- Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; 367:1783 – 1791.
8- Dieras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 2017; 18:732–742.
9- Von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 2019; 380:617–628.
10- Tolaney SM, Trippa L, Barry W, et al. TBCRC 033: A randomized phase II study of adjuvant trastuzumab emtansine vs paclitaxel in combination with trastuzumab for stage I HER2-positive breast cancer (ATEMPT). 2019 San Antonio Breast Cancer Symposium. Abstract GS1-05.
11- Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med 2020 Feb 13;382(7):610-621. doi: 10.1056/NEJMoa1914510. Epub 2019 Dec 11. PMID: 31825192; PMCID: PMC7458671.
12- Schalper KA, Kumar S, Hui P, et al: A retrospective population-based comparison of HER2 immunohistochemistry and fluorescence in situ hybridization in breast carcinomas: Impact of 2007 American Society of Clinical Oncology/College of American Pathologists criteria. Arch Pathol Lab Med 138:213-219, 2014
13- Burris HA, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011; 29:398 – 405.
14- Krop IE, LoRusso P, Miller KD, et al. A Phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol 2012; 30:3234 – 3241.
15- Modi S, Park H, Murthy RK, et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low – Expressing advanced breast cancer: results from a Phase Ib study. J Clin Oncol 2020; 38:1887 –1896.
16- Lin H, Huang JF, Qiu JR, et al. Significantly upregulated TACSTD2 and Cyclin D1 correlate with poor prognosis of invasive ductal breast cancer. Exp Mol Pathol 2013; 94: 73–78.
17- Bardia A, Mayer IA, Diamond JR, et al. Efficacy and safety of anti-trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J Clin Oncol 2017; 35: 2141–2148.
18- Bardia A et al. ASCENT: A randomized phase III study of sacituzumab govitecan versus treatment of physician’s choice in patients with previously treated metastatic triple-negative breast cancer. ESMO virtual congress 2020, LBA17.
19- Hurvirtz SA et al. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patient with metastatic triple-negative breast cancer. SABCS virtual congress 2020, GS3- 06.
20- Banerji U, van Herpen CM, Saura C, et al. Trastuzumab duocarmazine in & locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol 2019; 20:1124–1135.
21- Munster P, Krop IE, LoRusso P, et al. Safety and pharmacokinetics of MM-302, a HER2-targeted antibody-liposomal doxorubicin conjugate, in patients with advanced HER2-positive breast cancer: a phase 1 dose-escalation study. Br J Cancer 2018 Oct;119(9):1086-1093.
22- Miller K, Cortes J, Hurvitz SA, et al. HERMIONE: a randomized Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician's choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer. BMC Cancer. 2016 Jun 3;16:352.
23- Xu B, Wang J, Zhang Q, et al. An open-label, multicenter, phase Ib study to evaluate RC48-ADC in patients with HER2-positive metastatic breast cancer. J Clin Oncol 2018; 36(15_suppl):1028 – 11028
24- Pegram M, Hamilton E, Tan AR, et al. Phase 1 study of bispecific HER2 antibody-drug conjugate MEDI4276 in patients with advanced HER2-positive breast or gastric cancer. Ann Oncol 2018; 29:iii8.
25- Hamilton EP, Barve MA, Bardia A, et al. Phase 1 dose escalation of XMT- 1522, a novel HER2-targeting antibody-drug conjugate (ADC), in patients (pts) with HER2-expressing breast, lung and gastric tumors. J Clin Oncol 2018; 36(15_suppl):2546 – 12546.
26- Meric-Bernstam F, Calvo E, Moreno V, et al. A phase I dose escalation study evaluating the safety and tolerability of a novel anti-HER2 antibody-drug conjugate (PF-06804103) in patients with HER2-positive solid tumors. J Clin Oncol 2020 38:15_suppl, 1039-1039
27- Xia W, Petricoin EF III, Zhao S, et al. An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models. Breast Cancer Res 2013; 15: R85.
28- Ocana A, Vera-Badillo F, Seruga B, et al. HER3 overexpression and survival in solid tumors: a meta-analysis. J Natl Cancer Inst 2013; 105: 266–273.
29- Yonemori K, Masuda N, Takahashi S, et al. 151O. Single agent activity of U3-1402, a HER3- targeting antibody–drug conjugate, in HER3- overexpressing metastatic breast cancer: updated results from a phase I/II trial. Ann Oncol 2019; 30(Suppl. 3): iii48.
30- Taylor KM, Morgan HE, Johnson A, et al. Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. Biochem J 2003; 375: 51–59.
31- Modi S, Pusztai L, Forero A, et al. Phase 1 study of the antibody–drug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer. Clin Cancer Res 2018; 78(Suppl.): abstract PD3-14.
32- Lisberg AE, Sands J, Toshio Shimizu T, et al. Dose escalation and expansion from the phase I study of DS-1062, a trophoblast cell-surface antigen 2 (TROP2) antibody drug conjugate (ADC), in patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2020 38:15_suppl, 9619-9619
33- Sachdev JC, Maitland ML, Sharma M, et al. PF-06647020 (PF-7020), an antibody-drug conjugate (ADC) targeting protein tyrosine kinase 7 (PTK7), in patients (pts) with advanced solid tumors: results of a phase I dose escalation and expansion study [abstract]. J Clin Oncol 2018; 36(15_suppl): 5565–15565.
34- Gomez-Roca CA, Boni V, Moreno V, et al. A phase I study of SAR566658, an anti CA6- antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors (STs) (NCT01156870). J Clin Oncol 2016; 34(Suppl. 15): 2511.
35- Kearse KP, Smith NL, Semer DA, Eagles L, Finley JL, Kazmierczak S, et al. Monoclonal antibody DS6 detects a tumor-associated sialoglycotope expressed on human serous ovarian carcinomas. Int J Cancer 2000;88:
36- Tolcher A , Papadopoulos K, Cole Y, et al. A Phase 1a/2a trial of AVID100, an anti-EGFR antibody-drug conjugate. Ann Oncol 2018; 29(Suppl. 3): iii8.
37- Vahdat L, Forero-Torres A, Schmid P, et al. Abstract P6-20-01: METRIC: a randomized international phase 2b study of the antibody-drug conjugate (ADC) glembatumumab vedotin (GV) in gpNMB-overexpressing, metastatic, triple-negative breast cancer (mTNBC). Cancer Res 2019; 79(4 Supplement)P6-20-01.
38- Iwata TN, Ishii C, Ishida S, et al. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther 2018 Jul;17(7):1494-1503.