Emerging Therapies for HER2-Positive Metastatic Breast Cancer - Episode 7

Margetuximab for the Treatment of HER2+ Breast Cancer

Ian Krop, MD, PhD:There was an additional randomized phase III trial presented this year at San Antonio Breast Cancer Symposium, and that was involving another drug with a novel mechanism of action, called margetuximab. Margetuximab is essentially the same antibody as trastuzumab, meaning that it’s a HER2-directed monoclonal, but the difference is that several amino acids were changed in what’s called the Fc portion of the antibody. The Fc portion is the part of the antibody that binds to immune infector cells, and it’s felt to mediate the ability of trastuzumab or other HER2 monoclonal to activate NK [natural killer] cells to cause this immune effect called ADCC, or antibody-dependent cellular cytotoxicity. There’s also some suggestion that these antibodies can also activate T cells against the cancer as well. Again, that’s modulated via the Fc receptor.

The idea of margetuximab was to change the Fc portion of the antibody, so that it’s able to activate these NK cells and other immune effectors better. To test that, this trial looked at patients who had previously had HER2-directed therapy and randomized them to a chemotherapy of physician’s choice with either standard-of-care trastuzumab or margetuximab. What was reported at ASCO [the American Society of Clinical Oncology Annual Meeting] earlier this year was that those patients who got margetuximab and chemotherapy had a modest but statistically significant improvement in progression-free survival with the use of margetuximab compared to with trastuzumab.

In the analysis that was presented at San Antonio this year, this was updated. The progression-free survival benefit is still small but statistically significant. But they also looked at an updated overall survival analysis as well. This is not statistically significant, but it does trend toward better overall survival with margetuximab compared with trastuzumab. Interestingly, they looked at a subgroup of patients who have a specific genotype of their Fc receptors. This is a genotype that is less able to bind to trastuzumab to some extent.

In fact, 86% of the population in the trial had this lower-affinity Fc receptor, which in some studies had shown decreased benefit with trastuzumab. In this study, in those patients with the low-affinity receptors, the majority of the patients, there did seem to be somewhat more benefit of margetuximab compared with trastuzumab. That’s fitting with the scientific data that underlied the mechanism of action, margetuximab.

That’s somewhat surprisingly in patients who did not have the low-affinity receptor. For roughly 15% of patients, it actually looked like trastuzumab was superior to margetuximab. That was a little surprising. I’m not sure there’s a clear proposed mechanism for why trastuzumab would be better than margetuximab in that group, but that’s what was seen. It could be an artifact of small numbers—only 69 patients were in that group—but I think it requires further research. Certainly in those patients with the low-affinity Fc receptor, it does look like margetuximab could be an improvement over standard trastuzumab-based chemotherapy.

Fortunately, because trastuzumab and margetuximab are so similar, margetuximab does not add much in terms of toxicity. It has a very similar profile to trastuzumab. The 1 difference with margetuximab is that it does have somewhat higher rates of mild infusion reactions compared with trastuzumab.

This also could be beneficial for patients, and I think there’s room for improving on the benefits of margetuximab by combining it with other agents that may stimulate the immune system. It’s my understanding that some of those studies were moving on as well.

Transcript edited for clarity.