A New Kid on the Block: Sacituzumab Govitecan for the Treatment of Breast Cancer and Other Solid Tumors

Abstract

Human trophoblast cell-surface antigen-2 (Trop-2) is a membrane glycoprotein involved in cell proliferation and motility, frequently overexpressed in epithelial tumors. Thus, it represents an attractive target for anticancer therapies. Sacituzumab govitecan (SG) is a third-generation antibody-drug conjugate, consisting of an anti-Trop-2 monoclonal antibody (hRS7), a hydrolyzable linker, and a cytotoxin (SN38), which inhibits topoisomerase 1. Specific pharmacological features, such as the high antibody to payload ratio, the ultra-toxic nature of SN38, and the capacity to kill surrounding tumor cells (the bystander effect), make SG a very promising drug for cancer treatment. Indeed, unprecedented results have been observed with SG in patients with heavily pretreated advanced triple-negative breast cancer and urothelial carcinomas, and the drug has already received approval for these indications. These results are coupled with a manageable toxicity profile, with neutropenia and diarrhea as the most frequent adverse events, mainly of grades 1–2. While several trials are exploring SG activity in different tumor types and settings, potential biomarkers of response are under investigation. Among these, Trop-2 overexpression and the presence of BRCA1/2 mutations seem to be the most promising. We review the available literature concerning SG, with a focus on its toxicity spectrum and possible biomarkers of its response.

TROP2 Represents a Negative Prognostic Factor in Colorectal Adenocarcinoma and Its Expression Is Associated with Features of Epithelial–Mesenchymal Transition and Invasiveness

“…Therefore, there is a constant need to search for new predictive and prognostic CRC molecular markers. TROP2 is considered a promising therapeutic target in several other human malignancies [ 65 ]. Therefore, we used TMA to investigate the prognostic value of TROP2 in 292 retrospective CRC cases.…”

Theranostic application of 64Cu/177Lu-labeled anti-Trop2 monoclonal antibody in pancreatic cancer tumor models

“…Trop2 has stem cell-like properties to promote organ formation and embryonic development, and it plays a similar role in tumor cells participating in tumor growth, proliferation, and cell migration. The possible molecular mechanisms of Trop2 in tumor include regulating calcium signaling pathways and cyclin expression, participating in epithelial-mesenchymal transition (EMT) to reduce cell adhesion, and enabling tumor cells to acquire invasion and migration characteristics [18,19]. Trop2 is not or rarely expressed in normal tissues, making it an attractive therapeutic target due to limited toxicity [18].…”

Toxicity profile of antibody-drug conjugates in breast cancer: practical considerations

“… 32 Indeed, diarrhea is a toxicity of topoisomerase I inhibitors class, including SN-38 and DXd. 39 The main mechanism behind this toxicity is thought to be related to the early dissociation of the drug from its antibody, which leads to the diffusion of the active compound in normal tissues ( off-target off-tumor toxicity).…”