Antibody Drug Conjugates in Metastatic Breast Cancer

The clinical development of various antibody drug conjugates (ADCs) for patients with triple negative breast cancer was detailed in a presentation conducted by Aditya Bardia, MD, MPH at the 37th AnnualMiami Breast Cancer Conference, held from March 5-8, 2020 in Miami, Florida. 

ADCs consist of an antibody, which would preferably have high affinity and specificity to tumor antigen, efficient internalization, and reduced immunogenicity. There is then a linker, either a cleavable linker or a non-cleavable linker, that links the toxic payload to the antigen. A linker should be stable in the blood stream and capable of releasing payload once internalized. 

Within an ADC, you can have a highly or sometimes moderately potent payload according to Bardia, which can then be divided into 2 broad categories: microtubule inhibitors, such as auristatins and maytansines; or DNA damaging agents, such as calicheamicin, duocarmycins, and SN-38. All of these factors are important considerations that could potentially impact the efficacy and toxicity ratio of the antibody drug conjugate. 

“It’s important to understand the payload that is associated with the antibody drug conjugate because the antibody provides the specificity, but it’s the payload that ultimately provides the efficacy, and also it’s the payload that is usually responsible for the adverse events,” said Bardia.

The ADC works by binding to an antigen, then in turn getting internalized and degraded in the lysosome, where it then releases the payload and ultimately results in apoptosis of the cancer cell.

Presently, there are 4 targeting cell-surface markers for selective delivery of potent agents in triple negative breast cancer, Trop-2, LIV-1, HER2, and HER3. The targeting oncogenes for triple negative breast cancer are BRCA and PIK3CA, and the targeting key intracellular signaling pathways are the PI3K/AKT pathways.

Currently, sacituzumab govitecan is used to target Trop-2. In a phase I/II single-arm open-label study, as well as the phase III ASCENT study, Bardia along with other researchers, found that sacituzumab govitecan showed durable objective responses in pre-treated patients with metastatic triple negative breast cancer, with myelotoxicity being the major adverse effect.

Bardia also highlighted the ADC to target LIV-1, ladiratuzumab vedotin, which demonstrated a confirmed overall response rate of 25% (15/60) in a phase I study. Moreover, he explained that trastuzumab deruxtecan has been evaluated in multiple studies and is used to target HER2. Additionally, a phase I/III study of U3-1402 in HER3-positive metastatic breast cancer found the ADC to be effective based on preliminary safety and efficacy results. 

“The question is how can we further improve the response rates,” Bardia explained. “We saw a response rate of 30-40% with these antibody drug conjugates, can we improve that to 50, 60, 70, 80% and further improve the outcomes of patients with metastatic breast cancer.”

Moving forward, Bardia indicated that they are looking at ADC combination therapies, such as immunotherapy, and monotherapies in metastatic breast cancer, as well as potentially expanding ADCs into other settings. 

“Different antibody drug conjugations targeting different antigens would redefine the molecular classification of breast cancer in the future,” Bardia concluded. 

Reference:

Bardia A. Antibody Drug Conjugates: Present and Future. Presented at the 37th Annual Miami Breast Cancer Conference, held from March 5-8, 2020 in Miami, Florida.