Margetuximab Approval Augments Emerging Treatment Choices in Breast Cancer

Hope S. Rugo, MD, FASCO

Margetuximab-cmkb (Margenza) represents an effective new therapeutic option that can be combined safely with a chemotherapy drug of choice for patients with metastatic HER2-positive breast cancer who have undergone multiple lines of prior treatment, according to Hope S. Rugo, MD, FASCO.

In December 2020, the FDA approved margetuximab in combination with chemotherapy for adults with metastatic HER2-positive breast cancer who have received 2 or more prior anti-HER2 regimens, at least 1 of which in the met-astatic setting.¹ The decision capped a busy year in breast cancer approvals that included 2 new drugs and expand-ed indications for several previously approved agents (Timeline²).

The approval for margetuximab was based on findings from the phase 3SOPHIA trial (NCT02492711), in which 536 patients were randomized to receive either margetuximab or trastuzumab (Herceptin) plus physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.¹

After 24 months of treatment and follow-up, the median progression-free survival (PFS) by blinded independent central review was 5.8 months (95% CI, 5.5-7.0) for patients in the margetuximab arm and 4.9 months (95% CI, 4.2-5.6) for patients in the trastuzumab group (HR, 0.76; 95% CI, 0.59-0.98; P = .033).^1,3

In a second planned interim analysis conducted after 430 PFS events, investigator-assessed median PFS showed a 29% risk reduction with margetuximab therapy (HR, 0.707; 95% CI, 0.580-0.862; stratified log-rank P = .0006).³ In an analysis conducted after 270 deaths, median overall survival (OS) was 21.6 months (95% CI, 18.86-24.05) with margetuximab vs 19.8 months (17.54-22.28) with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33). Investigators expect the final OS analysis to be available in 2021, after 385 events occur.⁴

Rugo, a lead investigator on the SOPHIA trial, discussed the implications of the margetuximab approval in an interview. A 2020 Giants of Cancer Care^® award winner, Rugo is a professor of medicine and the director of Breast Oncology and Clinical Trials Education at UCSF Helen Diller Family Comprehensive Cancer Center.

OncLive: What does margetuximab bring to the table for patients with HER2-positive breast cancer?

Rugo: Margetuximab is a novel HER2-targeted antibody. Fc engineering was performed on the antibody that altered Fc receptor affinities. The Fab fragment has the same specificity and affinity and disrupts HER2 signaling similar to trastuzumab. But the Fc component of the antibody has been engineered to increase affinity for the activating Fcγ receptor (FcγR) IIIA, which is called CD16A, and to decrease the affinity for the inhibitory FcγRIIB, which is CD32B (Figure).

Figure. Mechanism of Action of Margetuximab

How does the structure of margetuximab contribute to its efficacy?

The intent of enhancing the affinity for certain IgG FcγRs and decreasing the affinity for the inhibitory receptors is to enhance innate immunity or antibody-dependent cellular cytotoxicity [ADCC] to increase CD16A engagement, which then would result in more potent ADCC stimulation. For the inhibitory factor, if you have less effect on the inhibitory receptor, you could enhance adaptive immunity with HER2-specific T-cell reactivity and antibodies.

Reduced CD32 binding theoretically would result in enhanced immune activation, which we know is very important for the activity of trastuzumab and now it appears other antibodies as well. In a phase 1 study (NCT01148849), some patients were able to stay on margetuximab for many years, even though they had trastuzumab-resistant disease when they started on study. Clearly, there is a unique effect of margetuximab in HER2 targeting.

What is striking about the responses to margetuximab in the SOPHIA trial?

There was a progression-free survival advantage that was statistically significant. That was the primary end point of the trial, but there has been some question about the magnitude of the difference in terms of the PFS analysis. In the investigator-assessed PFS end point with a cutoff of September 2019, the absolute PFS benefit of using margetuximab versus trastuzumab was under 2 months. But statistically, the hazard ratio was 0.71 and the P value was .0006. It was a highly statistically significant outcome, but it’s difficult when you’re looking at the median PFS to see the large differences that we’re used to seeing and like to see in HER2-positive disease.

Regardless, there were other secondary end points that supported this: a marked improvement in objective response rate, for example, from 13.7% to 25.2% [at the September 2019 cut-off], and in the patients who responded, a similar duration of response; so that getting a response seems to make a very big difference.

What is the potential impact of genotype on therapy response?

We looked at overall survival and PFS subgroups, but we also knew that CD16A biology could impact trastuzumab outcome. In adjuvant trials, it appeared that patients didn’t do quite as well with the addition of trastuzumab if they carried this low-affinity CD16A receptor, CD16A [genotypes containing a] 158F [allele]. This different binding affinity is very, very interesting.

This idea of looking at the patients who are F [allele] carriers is fascinating, and it’s being studied in an ongoing neoadjuvant trial. This was a prespecified, exploratory subset; we are not using this in decisions about which patients should receive margetuximab in the metastatic setting in combination with chemotherapy. The MARGOT trial (NCT04425018) in our [Translational Breast Cancer Research Consortium] is specifically enrolling patients who have an F allele. [Participants] are randomized to receive margetuximab or trastuzumab as their neoadjuvant primary HER2-targeted antibody. This is a good trial and will tell us a lot. You have untreated patients, and you’ll be able to see whether or not there is any difference in terms of the efficacy of margetuximab in a prospective trial based on their CD16 genotype. Patients also receive pertuzumab [Perjeta].

Where does margetuximab fit into the treatment landscape?

We’re thinking about using this in the later-line setting as we move pertuzumab as well as T-DM1 [ado-trastuzumab emtansine (Kadcyla)] to the earlier-stage setting and higher-risk disease, and we’re looking at moving fam-trastuzumab deruxtecan-nxki [Enhertu] and the tucatinib [Tukysa] triplet earlier. Margetuximab will be a next-line agent in combination with a menu of chemotherapy agents.

Today, margetuximab is moving forward as an option for treatment of patients with metastatic HER2-positive breast cancer. I think this question about whether or not we could select patients specifically based on their genotype to receive one antibody versus another is fascinating. We’ve really not made big headway in pharmacogenomics overall in breast cancer, so I think this is an exciting step.

How does the adverse effect profile of margetuximab compare with that of trastuzumab?

Overall, the number of adverse events with margetuximab versus trastuzumab was equivalent. Adverse events that were either chemotherapy- or antibody-related were similar, with the exception of infusion-related reactions. There were clearly more infusion-related reactions in patients who were treated with margetuximab vs trastuzumab. Now it’s important to remember that everybody who was in this trial had already received prior trastuzumab and pertuzumab, except for 1 patient, and over 90% had also received T-DM1, so they had already sort of had the test of time in terms of infusion reactions, which can also occur with the first infusion.

If you look at grade 3 or higher infusion reactions, there were 4 with margetuximab and 0 for trastuzumab out of about 265 patients in [each] arm, so they’re not very common. Overall, including grade 1 and grade 2, [infusion-related reactions] were 13.3% vs 3.4% for trastuzumab and margetuximab, [respectively].4 Most of them were easily controlled with premedications and certainly were controlled with rescue [therapy] at the time of developing these [adverse] effects. For the grade 3 or greater [infusion-related reactions], 2 of the patients discontinued therapy but, again, this was earlier in the trial and people weren’t really aware of how to manage this. With additional premedications, the other 2 patients continued on treatment.

Clearly, this is something we need to know about, but we can manage it. We see infusion-related reactions with a number of different antibody-based drugs that are approved. We always need to be aware of that when we’re infusing antibodies like this and be able to react and treat so that we can continue therapy.

Is there anything else important to note about administering this drug?

It’s probably worthwhile to start with some degree of premedication when you give margetuximab. Keep in mind as you start speeding up the infusion that you want to be sure that patients tolerate it with the first infusion, but also don’t be afraid if they do develop a reaction. You can stop, give additional medications, and usually complete the infusion or delay and give the infusion on a different day. That hasn’t been a big problem for us overall—it’s just important to know about. In terms of clinical practice, where we are using margetuximab—or thinking about it in terms of our sequencing of therapy—is after trastuzumab deruxtecan and after the tucatinib triplet....But it’s important to keep in mind that both of these agents have their own toxicities. [Some patients] might be eligible to receive margetuximab sooner.

References

1. FDA approves margetuximab for metastatic HER2-positive breast cancer. FDA. Updated December 17, 2020. Accessed February 26, 2021. https://bit.ly/3bEGXX2.
2. Hematology/oncology (cancer) approvals & safety notifications. FDA. Updated February 22, 2021. Accessed February 26, 2021. https://bit.ly/37OvLpm.
3. Center for Drug Evaluation and Research multi-discipline review. FDA. December 16, 2020. Accessed February 26, 2021. https://bit.ly/3q0a3Fj.
4. Rugo HS, Im SA, Cardoso F, et al; SOPHIA Study Group. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. JAMA Oncol. Published online January 22, 2021. doi:10.1001/jamaoncol.2020.7932