Breast Cancer Treatment and Antibody Drug Conjugates: Beyond T-DM1
Main Article Content
Abstract
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.
Keywords:
antibody–drug conjugates, breast cancer, HER2-positive, HER2-low, triple-negative
Article Details
How to Cite
UNG, Mony et al.
Breast Cancer Treatment and Antibody Drug Conjugates: Beyond T-DM1.
Medical Research Archives, [S.l.], v. 9, n. 8, aug. 2021.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2435>. Date accessed: 05 nov. 2024.
doi: https://doi.org/10.18103/mra.v9i8.2435.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1- Global Cancer Observatory, International Agency for Research on Cancer. Available from: https://gco.iarc.fr/
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:
866–72.
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.
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:
866–72.
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.