Antibody-drug Conjugates Targeting TROP-2: Clinical Development in Metastatic Breast Cancer

Overview

Journal Breast

Publisher Elsevier

Specialties Endocrinology
Oncology

Date 2022 Oct 27

PMID 36302269

Authors

Mythili Shastry

Saya Jacob

Hope S Rugo

Erika Hamilton

Affiliations

Soon will be listed here.

Abstract

Antibody drug conjugates (ADCs) combine the potent cytotoxicity of chemotherapy with the antigen -specific targeted approach of antibodies into one single molecule. Trophoblast cell surface antigen 2 (TROP-2) is a transmembrane glycoprotein involved in calcium signal transduction and is expressed in multiple tumor types. TROP-2 expression is higher in HER2-negative breast tumors (HR+/HR-) and is associated with worse survival. Sacituzumab govitecan (SG) is a first-in-class TROP-2-directed ADC with an anti-TROP-2 antibody conjugated to SN-38, a topoisomerase inhibitor via a hydrolysable linker. This hydrolysable linker permits intracellular and extracellular release of the membrane permeable payload enabling the "bystander effect" contributing to the efficacy of this agent. There was significant improvement in progression free survival (PFS) and overall survival (OS) with SG versus chemotherapy in pretreated metastatic triple negative breast cancer (TNBC), resulting in regulatory approval. Common adverse events (AE) reported were neutropenia and diarrhea. SG also demonstrated clinical activity versus chemotherapy in a phase III trial of HR+/HER2-metastatic breast cancer (MBC) and is under evaluation in first-line metastatic and early stage TNBC as well. Datopotamab deruxtecan (Dato-DXd) is a TROP-2 ADC that differs from SG in that it has a cleavable tetrapeptide linker and a more potent topoisomerase inhibitor payload. This construct is highly stable in circulation with a longer half-life than SG, and undergoes cleavage in presence of intracellular lysosomal proteases. Dato-DXd demonstrated preliminary efficacy in unselected metastatic TNBC, with common AEs of low-grade nausea and stomatitis. Dato-DXd is being investigated in phase III studies in metastatic TNBC and HR+/HER2- MBC. These novel TROP-2 ADCs have the potential to deliver enhanced efficacy with reduced toxicity in MBC and possibly in early stage breast cancer (EBC).

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References

Vidula N, Yau C, Rugo H . Trophoblast Cell Surface Antigen 2 gene (TACSTD2) expression in primary breast cancer. Breast Cancer Res Treat. 2022; 194(3):569-575. DOI: 10.1007/s10549-022-06660-x. View

Goldenberg D, Stein R, Sharkey R . The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget. 2018; 9(48):28989-29006. PMC: 6034748. DOI: 10.18632/oncotarget.25615. View

Drake P, Rabuka D . An emerging playbook for antibody-drug conjugates: lessons from the laboratory and clinic suggest a strategy for improving efficacy and safety. Curr Opin Chem Biol. 2015; 28:174-80. DOI: 10.1016/j.cbpa.2015.08.005. View

Mahalingaiah P, Ciurlionis R, Durbin K, Yeager R, Philip B, Bawa B . Potential mechanisms of target-independent uptake and toxicity of antibody-drug conjugates. Pharmacol Ther. 2019; 200:110-125. DOI: 10.1016/j.pharmthera.2019.04.008. View

Trerotola M, Cantanelli P, Guerra E, Tripaldi R, Aloisi A, Bonasera V . Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene. 2012; 32(2):222-33. DOI: 10.1038/onc.2012.36. View

Ambrogi F, Fornili M, Boracchi P, Trerotola M, Relli V, Simeone P . Trop-2 is a determinant of breast cancer survival. PLoS One. 2014; 9(5):e96993. PMC: 4019539. DOI: 10.1371/journal.pone.0096993. View

Strop P, Tran T, Dorywalska M, Delaria K, Dushin R, Wong O . RN927C, a Site-Specific Trop-2 Antibody-Drug Conjugate (ADC) with Enhanced Stability, Is Highly Efficacious in Preclinical Solid Tumor Models. Mol Cancer Ther. 2016; 15(11):2698-2708. DOI: 10.1158/1535-7163.MCT-16-0431. View

Kalinsky K, Diamond J, Vahdat L, Tolaney S, Juric D, OShaughnessy J . Sacituzumab govitecan in previously treated hormone receptor-positive/HER2-negative metastatic breast cancer: final results from a phase I/II, single-arm, basket trial. Ann Oncol. 2020; 31(12):1709-1718. DOI: 10.1016/j.annonc.2020.09.004. View

Lipinski M, Parks D, Rouse R, Herzenberg L . Human trophoblast cell-surface antigens defined by monoclonal antibodies. Proc Natl Acad Sci U S A. 1981; 78(8):5147-50. PMC: 320350. DOI: 10.1073/pnas.78.8.5147. View

10.

Stepan L, Trueblood E, Hale K, Babcook J, Borges L, Sutherland C . Expression of Trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target. J Histochem Cytochem. 2011; 59(7):701-10. PMC: 3201164. DOI: 10.1369/0022155411410430. View

11.

Rispens T, Davies A, Ooijevaar-De Heer P, Absalah S, Bende O, Sutton B . Dynamics of inter-heavy chain interactions in human immunoglobulin G (IgG) subclasses studied by kinetic Fab arm exchange. J Biol Chem. 2014; 289(9):6098-109. PMC: 3937676. DOI: 10.1074/jbc.M113.541813. View

12.

Rugo H, Bardia A, Tolaney S, Arteaga C, Cortes J, Sohn J . TROPiCS-02: A Phase III study investigating sacituzumab govitecan in the treatment of HR+/HER2- metastatic breast cancer. Future Oncol. 2020; 16(12):705-715. DOI: 10.2217/fon-2020-0163. View

13.

Mach J, Carrel S, Forni M, Ritschard J, Donath A, Alberto P . Tumor localization of radio-labeled antibodies against carcinoembryonic antigen in patients with carcinoma: a critical evaluation. N Engl J Med. 1980; 303(1):5-10. DOI: 10.1056/NEJM198007033030102. View

14.

Iwata T, Ishii C, Ishida S, Ogitani Y, Wada T, Agatsuma T . A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018; 17(7):1494-1503. DOI: 10.1158/1535-7163.MCT-17-0749. View

15.

Rugo H, Tolaney S, Loirat D, Punie K, Bardia A, Hurvitz S . Safety analyses from the phase 3 ASCENT trial of sacituzumab govitecan in metastatic triple-negative breast cancer. NPJ Breast Cancer. 2022; 8(1):98. PMC: 9424318. DOI: 10.1038/s41523-022-00467-1. View

16.

Bardia A, Tolaney S, Punie K, Loirat D, Oliveira M, Kalinsky K . Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Ann Oncol. 2021; 32(9):1148-1156. DOI: 10.1016/j.annonc.2021.06.002. View

17.

Shvartsur A, Bonavida B . Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer. 2015; 6(3-4):84-105. PMC: 4426947. DOI: 10.18632/genesandcancer.40. View

18.

Kawato Y, Aonuma M, Hirota Y, Kuga H, Sato K . Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res. 1991; 51(16):4187-91. View

19.

Junttila T, Li G, Parsons K, Phillips G, Sliwkowski M . 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. 2010; 128(2):347-56. DOI: 10.1007/s10549-010-1090-x. View

20.

Starodub A, Ocean A, Shah M, Guarino M, Picozzi Jr V, Vahdat L . First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors. Clin Cancer Res. 2015; 21(17):3870-8. PMC: 4558321. DOI: 10.1158/1078-0432.CCR-14-3321. View