Sandra Cuellar, PharmD, BCOP, FASHP, on Infusion-Related Reactions With Margetuximab for HER2+ Metastatic Breast Cancer

For the latest installment of the “Product Profile”, ONCOLOGY® spoke with Sandra Cuellar, PharmD, BCOP, FASHP, about margetuximab (Margenza) as therapy for patients with HER2-positive metastatic breast cancer. Here, she discusses the SOPHIA trial (NCT02492711) and the occurrence of grade 1 and grade 2 infusion-related reactions.

Transcript:

Margetuximab is an antibody that targets HER2. Two things are really important to highlight about the safety profile of margetuximab that were observed in the SOPHIA trial [NCT02492711]. First, the infusion-related reactions: About 13% of patients in SOPHIA experienced infusion-related reactions, primarily grade 1 and grade 2 [in severity]. When compared with trastuzumab in that study, only about 3% experienced infusion-related reaction.

In the real world, we really don’t see infusion-related reactions with trastuzumab. It’s not very common with trastuzumab and we don’t premedicate [for it] with trastuzumab. However, I’m not really surprised by that in the sense that in the nomenclature of these drugs, we know that there is a difference. Trastuzumab is a humanized monoclonal antibody, as indicated by the “-zu” in the nomenclature. Margetuximab is a chimeric monoclonal antibody, as indicated by “-xu” in the nomenclature. Infusion-related reactions are more commonly seen with chimeric monoclonal antibodies because of that murine base compared with humanized monoclonal antibodies. This can partially explain the difference in higher incidence of infusion-related reactions with margetuximab compared to trastuzumab. Another possible reason for increased infusion related reactions maybe related with its mechanism of action with an enhanced immune immune response.

Infusion-related reactions in the SOPHIA trial primarily happened in cycle 1, and with subsequent cycles if [disease was] low grade 1 or grade 2. We were able to add pre-medications to manage those [such as] antihistamines, antipyretics, and corticosteroids. Another recommendation that is slowing the infusion. 

It’s important that we all think about cardiotoxicity with any HER2-directed monoclonal antibody. We associate cardiotoxicity with any monoclonal antibody that targets HER2; we see that with trastuzumab or pertuzumab. What does that cardiotoxicity look like with margetuximab? Does this FC-engineered component add or worsen cardiotoxicity? What we’ve seen and what’s been published [show that] it does not appear that it has any more cardiotoxicity than trastuzumab. In the clinical trials, about 3% of patients experience a decline in the ejection fraction, which was similar to trastuzumab.

This agent was approved in December 2020, and no additional safety pharmacovigilance reports that I’m aware of that say that there’s more cardiotoxicity than what was observed in the clinical trial. Also, it had similar cardiotoxicity in terms of lower ejection fraction [and] it was reversible, like what we see with trastuzumab and other HER2[-targeted] monoclonal antibodies. In the clinical trials, it is primarily asymptomatic. These declines in ejection fraction were observed via monitoring, not because the patient was symptomatic.1,2

Reference

Rugo HS, Im SA, Cardoso F, et al. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. JAMA Oncol. 2021;7(4):573-584. doi:10.1001/jamaoncol.2020.7932