Clinical Development of New Antibody–Drug Conjugates in Breast Cancer: To Infinity and Beyond

Abstract

Metastatic breast cancer remains an incurable disease, and new therapies are needed. One major limitation of chemotherapy is the toxicity associated with higher dose exposure. Antibody-drug conjugates (ADCs) are a complex and evolving class of agents specifically designed with the objective of delivering antineoplastic medicines in the most precise and selectively targeted way. ADCs are composed of four key components: (1) the target antigen, (2) an antibody construct, (3) a payload (most commonly a cytotoxic agent), and (4) a linker moiety that couples the payload and the antibody. In this review, we discuss the clinical development of ADCs for the treatment of breast cancer, focusing on two recently FDA-approved agents, trastuzumab deruxtecan and sacituzumab govitecan, and discuss the ongoing efforts exploring new agents. Finally, we summarize the current portfolio of clinical trials that could change the algorithm of treatment for early and advanced breast cancer.

Anti-tumor efficacy of an MMAE conjugated antibody targeting cell surface TACE/ADAM17-cleaved Amphiregulin in breast cancer

“…The value of ADCs is the specific delivery to a tumor of drugs that may be too toxic for patients or have complicating side effects if given at a dose high enough for tumor eradication. At least 34 unique ADCs are in various stages of clinical trials in the United States for treating solid tumors, with only three being FDA approved for clinical use in breast cancer at the time of publication: two targeting HER2 (trastuzumab emtansine, trastuzumab deruxtecan) and sacituzumab govitecan, which targets Trop-2 in metastatic TNBC patients (Barroso-Sousa and Tolaney, 2021). ADC development in breast cancer has mostly been directed towards HER2+ disease, with relatively little attention given to ER+ disease due to a paucity of targets.…”

Sacituzumab govitecan and trastuzumab deruxtecan: two new antibody–drug conjugates in the breast cancer treatment landscape

“…Several other Ags are considered in the pipeline of ADCs in BC, among which are LIV-1 and HER3. 12 Despite the fact that the magnitude of benefit seems to outweigh toxicity in the majority of patients resulting in a favorable benefit/risk profile, awareness of the unique safety profile of both drugs is crucial for optimal management of patients treated with these novel ADCs. Regarding hematological toxicity, almost half of the patients treated with SG in ASCENT received G-CSF, which should be considered when implementing this drug in clinical practice.…”

“…13 The drug class of ADCs is rapidly expanding and is expected to become the next drug wave in oncology. 9,12,13 In 2013, ADCs made their introduction as treatment option for advanced solid tumors with the Food and Drug Administration (FDA) approval of ado-trastuzumab emtansine (T-DM1, Kadcyla®) for metastatic HER2þ BC pretreated with trastuzumab and a taxane, based on results from the phase III EMILIA trial. 14,15 T-DM1 also proved its value in later-line advanced setting and in the adjuvant setting in patients with residual disease after neoadjuvant trastuzumab and taxanes.…”

“…The ADC–Ag complex is internalized and incorporated into endosomes or lysosomes, where the payload is released through proteolytic degradation of the entire ADC molecule or due to cleavage of the linker, which can be provoked by extracellular or intracellular conditions. 12 The payload then binds to its intracellular target such as tubulin, DNA or topoisomerase 1. Membrane permeability for the payload and linker instability can cause off-target effects on nearby Ag-positive and Ag-negative cells, which is called the bystander effect.…”

“… 13 The drug class of ADCs is rapidly expanding and is expected to become the next drug wave in oncology. 9 , 12 , 13 …”