Margetuximab for the treatment of HER2-positive metastatic breast cancer

Abstract

Introduction:No specific standard treatment is currently recommended for HER2-positive advanced breast cancer (BC) patients progressing to dual HER2 blockade and to trastuzumab emtansine (TDM-1). However, several novel anti-HER2 agents are emerging and rapidly revolutionizing this setting. Among these, the FC-engineered monoclonal antibody margetuximab has recently demonstrated to slightly improve progression-free survival (PFS) compared with trastuzumab, when combined with chemotherapy for pretreated HER2-positive advanced BC. Areas covered: The present review article recapitulates the clinical development of margetuximab, critically discussing its implications in the current landscape of BC treatment algorithms. Expert opinion:The clinical role of Margetuximab can only be interpreted in view of the rapidly evolving treatment landscape for pretreated HER2-positive advanced BC. Indeed, the recently approved anti-HER2 agents tucatinib and trastuzumab deruxtecan currently represent appealing options for the post-TDM1 setting, while margetuximab may have a role after progression to the abovementioned agents, in case of a future approval. Regardless of its clinical uptake, it should be noted that the development of margetuximab has relevantly improved our biological understanding of HER2-positive BC, highlighting the implication of patient's genotype in determining treatment outcomes, as well as the relevance of antibodydependent cellular cytotoxicity (ADCC) in the context of HER2-blockade.

Brain Metastases in HER2-Positive Breast Cancer: Current and Novel Treatment Strategies

“…Margetuximab is a chimeric IgG1 monoclonal antibody that holds the same epitope specificity of trastuzumab. However, its fragment crystallizable (Fc) domain has been modified to improve affinity for CD16A and reduce affinity for CD32B, resulting in better ADCC activity over trastuzumab in vitro [70].…”

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

“…Along with the studies pinpointing the ways to overcome the resistance towards currently employed antibodies targeting the HER2 receptor, other strategies are applied to improve the functionality of these antibodies. In the case of margetuximab, a modification in the Fc region was introduced that leads to increased NK cell activation and enhanced induction of antibody-dependent cellular cytotoxicity (ADCC) resulting in slightly better clinical outcome (HR 0.76; 95% CI, 0.59 to 0.98; p = 0.033) [ 84 ]. Moreover, other approaches based on the combination of unique antibodies and novel drugs have been also developed, such as ado-trastuzumab emtansine (T-DM1) [ 85 ] alone or in combination with drugs (e.g., ARX788 [ 86 ]), trastuzumab deruxtecan [ 87 ], or administration of DS-8201a in patients previously treated with T-DM1 [ 88 ].…”

Breast Cancer Treatments: Updates and New Challenges

“…It is based on trastuzumab as it binds to the same epitope (subdomain IV or HER2 extracellular domain) but with an enhanced Fcγ domain. The substitution of five amino acids into the IgG1 Fc domain increases CD16A affinity, a receptor found on macrophages and natural-killer cells, and decreases CD32B affinity, leading to increased antibody-dependent cell-mediated cytotoxicity (ADCC) [ 285 ]. A phase I study evaluated margetuximab toxicity and tumor activity on HER2+ BC patients for whom no standard treatment was available [ 266 ].…”