Expert Commentary on the Product Profile of Margetuximab for HER2-Positive Breast Cancer

Oncology, ONCOLOGY Vol 35, Issue 9,
Pages: 573

In an interview with ONCOLOGY®, Sandra Cuellar, PharmD, BCOP, FASHP, offers a comprehensive review of real-world treatment considerations of margetuximab as therapy for adult patients with metastatic HER2-positive breast cancer who have received 2 or more prior anti-HER2 regimens with at least 1 being for metastatic disease.

Q: Can you briefly describe margetuximab’s mechanism of action?

A: The mechanism of action of margetuximab [Margenza] is exciting; we’re now moving into this new era of monoclonal antibody technology. We’ve been using monoclonal antibodies since the 1990s, and the way I teach [about] them in school is [that there are] naked monoclonal antibodies, the first ones at least; now, we’ve advanced to antibody-drug conjugates, where we’re tacking on a cytotoxic component, and bispecific monoclonal antibodies [that] have dual binding. When we talk about the mechanism of action of margetuximab, it’s a bispecific monoclonal antibody, and it has 2 binding sites. It has one binding that targets the HER2 receptor. It’s been genetically modified and engineered to bind to the natural killer [NK] cell. What’s exciting about this mechanism of action is that we’re building on this technology with this dual binding, so we’re enhancing this basic monoclonal antibody that we’ve been using, at least with trastuzumab [Herceptin], since the 1990s.

More specifically, the mechanism of action of margetuximab is that it targets the HER2 receptor, the extracellular domain, and the FC [fragment crystallizable] component of that monoclonal antibody has been genetically engineered to target and bind to the NK cell. When it binds to the NK cell, the idea is that you’re enhancing the antibody-dependent cellular cytotoxicity. Margetuximab has the same binding, as well as binding affinity, to the HER2 receptor as trastuzumab. We have 2 monoclonal antibodies, trastuzumab and margetuximab, binding to the same site with a similar binding affinity to that receptor, which is different from pertuzumab [Perjeta].

Q: What are some of the concerns with margetuximab’s toxicity profile? Have any new safety concerns become more apparent with its use in the real-world treatment setting?

A: 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 with trastuzumab. Another possible reason for increased infusion-related reactions may be related to its mechanism of action with an enhanced 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. To manage those, we were able to add premedications [such as] antihistamines, antipyretics, and corticosteroids. Another recommendation 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 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

Q: What are some of the risks of left ventricular dysfunction associated with this agent?

A: [Speaking specifically about] left ventricular dysfunction, just knowing the mechanism of action [of this agent and] that it targets the HER2 receptor, we know that there will be, just from the mechanistic perspective, some level of cardiotoxicity, given our [experience with] previous agents. Again, margetuximab had about 3% of cardiotoxicity, primarily manifesting as decrease in ejection fraction, [which was] asymptomatic and reversible. The management is [similar to what] we do with trastuzumab. If it’s greater than or equal to a 16% drop from pretreatment ejection fractions, you’re going to hold [the drug] and at that point, you should consult a cardio-oncologist. Once it recovers, you can restart.

Q: Are dosing modifications common with the use
of margetuximab?

A: Because margetuximab is a monoclonal antibody, the dosing adjustments are primarily centered around [ejection fraction]. The recommendation is to get a baseline [echocardiogram] or ejection fraction and to continue monitoring that every 3 months. If you do see a decline in the ejection fraction greater than or equal to 16%, you’re going to hold and wait for it to recover. In terms of dosing adjustments, it’s pretty much like all monoclonal antibodies: Either give or you don’t give. When you hold, it’s because of a decrease or a significant increase in ejection fraction or for more severe infusion-related reactions. There are no hepatic or renal adjustments. This was given in combination with chemotherapy. If a patient experiences neutropenia or diarrhea, it’s likely because of the chemotherapy component vs margetuximab. This agent has a very similar [adverse] effect profile to trastuzumab, with the exception of the infusion-related reactions; we’re seeing those be a little bit more enhanced with margetuximab.

Q: Are there any major drug interactions with margetuximab that clinicians should be aware of?

A: Margetuximab skips the cytochrome P450 pathway. The important drug interactions are with other cardiotoxic drugs. In the breast cancer world, the primary drug interaction here would be doxorubicin. You would not want to give this drug concomitantly with doxorubicin. I would say it’s contraindicated, similar [to] trastuzumab. No anthracycline would be recommended concomitantly with margetuximab because of the additional additive cardiotoxic toxicity.

Q: Have any barriers to administration or receipt by the patient emerged since this agent’s approval, such as common reimbursement issues or logistical challenges to obtaining the medication?

A: Margetuximab was approved in December 2020, and [so far], in terms of access or administration, we have observed no real challenges or barriers with access or administration. We are just on the lookout for those infusion-related reactions in the 13% of patients who get them. When we were building our EPIC protocol, that was a question: “Do we automatically just give some premedications? Or do we watch and wait?” But no, there are no major barriers or access issues with this agent. It’s a welcome addition to patients in the third-line and beyond setting [with] metastatic HER2-positive breast cancer.n

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References

  1. 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
  2. Margetuximab. Prescribing information. Macrogenics; 2020. Accessed August 23, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761150s000lbl.pdf