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Certain Fc receptor genotypes are associated with weaker binding between immune effector cells and the Fc portion of an antibody. Patients with these genotypes may generate a less robust antitumor immune response when receiving antibody-based therapies.
Margetuximab is an antibody very similar to trastuzumab but with the Fc portion engineered to bind more tightly to Fc receptors, theoretically leading to enhanced antibody-dependent cellular cytotoxicity.[54-57] Compared with trastuzumab, this novel agent has increased affinity for the activating Fcγ receptor RIIIA (CD16A) and decreased affinity for the inhibitory Fcγ receptor RIIB (CD32B).
Following promising results from preclinical and early-phase clinical studies, margetuximab plus chemotherapy was compared with trastuzumab plus chemotherapy in the randomized, open-label phase III SOPHIA study. In SOPHIA, 536 patients with HER2-positive MBC, at least 2 previous HER2-targeted therapies, and up to 3 previous lines of therapy for metastatic disease were randomized to receive margetuximab or trastuzumab plus standard-of-care chemotherapy (investigator’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine). The study design included a sequential primary endpoint of PFS and OS; secondary endpoints included ORR and investigator-assessed PFS.
The primary endpoint of median PFS in the intention-to-treat population (by blinded analysis) demonstrated a small but significant improvement of nearly 1 month for margetuximab over trastuzumab (5.7 vs 4.4 months, respectively; HR: 0.71; P = .0006), corresponding to a 29% reduction in the risk of progression. This finding seems modest in comparison to the very large PFS improvements we are accustomed to seeing for new agents in this setting.
In both the first and second interim OS analyses of the intention-to-treat population, the median OS was similar between treatment groups. The first analysis found a median OS of approximately 18 months in October 2018, and the second analysis found a median OS of approximately 20 months in September 2019.
However, there was a separation of the curves in favor of margetuximab for patients who were CD16A-158F carriers, with the difference between arms reaching almost 7 months (median OS: 23.6 with margetuximab plus chemotherapy vs 16.9 months with trastuzumab plus chemotherapy; HR: 0.82). This benefit may be due to the re-engineered antibody overcoming poor affinity for Fc. As an exploratory analysis, this was a nice proof of principle; however, these findings are hypothesis generating and do not impact clinical practice outside of the setting of a clinical trial at this time.
AE rates were very similar for margetuximab vs trastuzumab, with the caveat that slightly more grade 3/4 fatigue, nausea, and neutropenia were seen with margetuximab. The most common grade 3/4 event was neutropenia, affecting 19.3% of patients in the margetuximab arm vs 11.9% of patients in the trastuzumab arm. Of note, 4 patients had grade 3/4 infusion-related reactions with margetuximab as compared with only grade 1/2 infusion-related reactions with trastuzumab. Overall, the arms were fairly similar in terms of tolerability.
I am not certain whether these data will support FDA approval of margetuximab in this setting, but clearly there is some interest in this agent because of the benefit in patients who are CD16A-158F carriers. Indeed, 86% of the genotyped patients in this trial were found to be CD16A-158F carriers. In the future, one possibility is that testing for this allele could be used to guide specific treatment recommendations in the neoadjuvant setting.