SOPHIA: Margetuximab and chemo versus trastuzumab and chemo in HER2 positive MBC after prior anti-HER2 therapies

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Published: 10 Jun 2019
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Prof Hope Rugo - University of California, San Francisco, USA

Prof Hope Rugo talks to ecancer at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting about the primary analysis from the phase III randomised SOPHIA trial which compares margetuximab and chemotherapy with FOLFOXIR I in HER2 positive metastatic breast cancer (MBC) after prior anti-HER2 therapies.

She explains that margetuximab is an antibody, novel to HER2, which is designed to activate the immune response, something which is of great importance to trastuzumab efficacy.

Prof Rugo reports that progression free survival was prolonged in patients randomised to receive margetuximab over trastuzumab and, although the difference was small, it was statistically significant.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

The SOPHIA trial is a randomised phase III trial testing a novel antibody to HER2 in patients with pre-treated HER2 positive metastatic breast cancer. Margetuximab is actually an antibody which shares the Fab component with trastuzumab but for the Fc component it has been engineered to improve binding, or improve the affinity, for IgG Fc-gamma receptors that activate the immune system. So this is an antibody designed to activate the immune response which we know is really important for trastuzumab efficacy. What margetuximab has been shown to do in the in vitro setting is it has increased affinity for these activating IgG Fc-gamma receptors and we know that there are alleles or polymorphisms that have higher or lower affinity. Specifically margetuximab has a good affinity for both the high and low affinity Fc-gamma receptors. There are also inhibitory receptors, Fc-gamma inhibitory receptors, and margetuximab has a lower affinity for the inhibitory receptors so that it would presumably have less activation of the inhibitory factors that push down the immune system. In addition in pre-clinical studies looking at NK cells we’ve seen an increased activation of the immune response in the cells that carry the low affinity Fc-gamma alleles compared to trastuzumab. So it’s compared to a relatively comparable trastuzumab antibody and it suggests that there may be variable efficacy of margetuximab that favours the population that have an increase in the low affinity IgG Fc-gamma receptors.

So a phase I study was done with margetuximab and included a small number of women with metastatic breast cancer. Their overall response rate was 17% and there were actually a few patients who remain on treatment now for over four years. They looked at peripheral blood mononuclear cells and found that there was an increase in T-cells that were active against specific HER2 antigens when patients received margetuximab which is really encouraging and it suggests that margetuximab is having the immune effect that we wanted it to have.

So based on all this data the hypothesis was that margetuximab in a HER2 positive pre-treated population would have greater efficacy compared to trastuzumab and specifically would have greater efficacy in the low affinity activating IgG Fc-gamma receptor positive population. So the trial actually randomised over 500 women with HER2 positive metastatic breast cancer who had received one to three lines of prior therapy and at least two prior HER2 targeted treatments. They had to have received trastuzumab and pertuzumab. Patients were randomised to receive either margetuximab or trastuzumab in combination with chemotherapy. The primary endpoint was progression free survival by blinded independent central analysis.

What we found actually in this population of patients was that progression free survival by blinded analysis was prolonged and significantly so in patients receiving margetuximab compared to trastuzumab. However, this difference was very small, although statistically significant, at just about one month. When we looked at the subgroup of patients based on their IgG Fc-gamma receptor alleles we found that there was a suggestion of a difference in patients who had different alleles for CD16A. In patients who had CD16A F allele there was an amplification of the margetuximab effect on progression free survival whereas in patients who were homozygous for the V high affinity allele it appeared that margetuximab and trastuzumab were relatively similar. Actually about 85% of the population have at least one F allele so this could be a major impact favouring margetuximab in a patient population who have more of the low affinity activating Fc-gamma receptor allele.

Then we had a first interim analysis on overall survival. There aren’t enough events yet and there is no difference in the intent to treat analysis but we took an initial look in this pre-planned exploratory subset analysis looking at cd16A alleles. What we found is that in the population of patients who carry an F allele that there is a numerically large difference in overall survival. This is very exciting data, it’s very early and too early to make any specific claims but we’ll have a second interim analysis later in 2019 and hopefully we’ll have data by the end of the year.

Of course we also looked at safety and margetuximab appears to be relatively similar to trastuzumab in terms of safety. The only difference was an increase in infusion related reactions which were generally easily managed by pre-medications. Of course patients who were in the trastuzumab arm had previously been treated with trastuzumab so they don’t have infusion related reactions. If you look at earlier data with trastuzumab patients did have infusion related reactions. If you give pre-medications to those patients or slow down the infusion you can generally manage their reactions fairly well.

So, in summary, the SOPHIA trial showed very interesting data with a novel Fc engineered HER2 antibody that suggests that it may have improved efficacy in the population of patients who carry a low affinity Fc-gamma CD16A allele. We’ll see more data that will give us better and firmer information on this towards the end of this year.