Rugo Shares Insight on Intriguing SOPHIA Data in HER2+ Breast Cancer

Hope Rugo, MD

Margetuximab, a novel Fc-engineered HER2-targeted antibody, showed improved progression-free survival (PFS) compared with trastuzumab (Herceptin) in patients with pretreated HER2-positive metastatic breast cancer in the open-label phase III SOPHIA trial, explained Hope S. Rugo, MD, adding that the agent is said to have significant immune activity.

Results showed that the median PFS for patients who received margetuximab was 5.8 months versus 4.9 months for those who received trastuzumab (HR, 0.76; P = .033). Additionally, overall survival (OS) in the intent-to-treat population was 18.9 months in the margetuximab arm versus 17.2 months in the trastuzumab arm (HR, 0.95; 95% CI, 0.69-1.31).

The PFS was even greater in patients were carriers of the CD16A-F allele. In this subgroup, data from a planned exploratory PFS analysis showed that the median PFS was 6.9 months in patients randomized to margetuximab versus 5.1 months in those who received trastuzumab (HR, 0.68; P = .005).

“[The SOPHIA] trial was based on the hypothesis that margetuximab might have greater activity in patients who had specific high affinity Fc-gamma receptor alleles. We also had a preplanned subset analysis looking at patients' polymorphisms for the IgG Fc-gamma receptors, specifically looking at high and low affinity alleles,” said Rugo, clinical professor, Department of Medicine, and director, Breast Oncology Clinical Trials Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

In an interview with OncLive, Rugo discussed the findings from the phase III SOPHIA trial and the potential impact of margetuximab on HER2-positive metastatic breast cancer.

OncLive: Could you provide some background on margetuximab and its place in HER2-positive breast cancer treatment?

Rugo: Margetuximab is a novel HER2-targeted antibody, which shares the fragment antigen-binding with trastuzumab. However, the Fc portion of the antibody has been engineered to increase the affinity for the Fc-gamma receptor alleles. If you increase the affinity, activating alleles of the Fc-gamma receptor for IgG, you may enhance the ability of the antibody to bind in the activated immune response, which will then translate into improved antitumor spots. At the same time, margetuximab has been engineered to reduce affinity for the inhibitory IgG Fc-gamma receptor alleles.

In a phase I study, margetuximab demonstrated responses in the subset of heavily pretreated patients who have HER2-positive metastatic breast cancer. Interestingly, several of these patients continued on antibody therapy for over 4 years. Studies performed on peripheral blood mononuclear sites in patients in the phase I setting demonstrated increased responses to a number of different HER2 antigens. Supporting preclinical data suggest that margetuximab may have additional immune-activating properties compared with trastuzumab.

Moving onto the SOPHIA trial, what was the design of this study?

Because of these data, [the phase III SOPHIA trial] was designed and randomized women who had received at least 2 prior lines of HER2-targeted therapy and 1 to 2 lines of prior treatment in the metastatic setting. That trial confirmed that patients with HER2-positive metastatic breast cancer could receive margetuximab or trastuzumab in combination with a menu of standard chemotherapy agents. The primary endpoint was PFS by blinded independent central analysis. There were also a number of secondary endpoints.

The trial enrolled more than 500 patients. All patients, by protocol design, had received prior trastuzumab and pertuzumab. About 91% of patients had received prior ado-trastuzumab emtansine (T-DM1; Kadcyla). The PFS rate, by blinded independent central analysis, was longer in patients receiving margetuximab than those receiving trastuzumab. This was specifically significant, although the clinical difference was only about 1 month. Similar data was found with investigator-assessed PFS.

Based on the hypothesis and the preplanned exploratory subset analysis looking at IgG Fc-gamma receptors, we found that the CD16A alleles might impact the efficacy of margetuximab. We analyzed this further. About 85% of the population has a low affinity F allele, whereas the remaining portion of the population are homozygous for the V high affinity allele. Prior retrospective studies have resulted in controversial data about the efficacy of trastuzumab based on the IgG Fc-gamma receptors CD16A-F and V alleles. Those 2 studies suggest that trastuzumab has less efficacy in patients who carried the low affinity F allele because of less binding. However, there are 2 studies suggesting that it might not have made a difference.

SOPHIA is the first prospective trial, in which we designed a substudy to look at the impact of these Fc-gamma receptor alleles. When we look at PFS in the patients who are homozygous for the high affinity allele, it appeared margetuximab and trastuzumab had relatively similar results for PFS. However, when we looked at patients who carried a CD16A-F allele, it appeared that in this group of patients, the PFS benefit of margetuximab was amplified. When we looked at the patients who were homozygous for low affinity F allele, the FF versus the FV group were heterozygous. It appeared that the effect was even further amplified.

At the time of this presentation, we have the first interim OS analysis. Looking at the intent-to-treat population, there's no difference in OS. However, in this preplanned exploratory subset analysis, we looked at the effect of the CD16A-F and V alleles on OS. It was exploratory and only the first interim analysis, but there was a marked difference numerically in OS in patients who carried an CD16A-F allele, either FF or FV.

We planned a second interim analysis of OS later in 2019 and hope to have data by the end of the year. This will provide much more information about the impact of the CD16A-F allele for the IgG Fc gamma receptor on the impact of OS.

What is the safety profile for margetuximab?

In terms of safety, margetuximab was relatively similar to trastuzumab. The only exception was an increase in fusion-related reaction, which was generally well managed. Everyone who had received trastuzumab on the trial had already received trastuzumab in the past, and therefore they were not expected to have an infusion-related reaction. However, the event rate that we saw in the SOPHIA trial for margetuximab was similar to earlier reports of trastuzumab. In general, patients were able to continue treatment despite these infusion reactions, although a small number of patients discontinued therapy.

Based on these data, margetuximab is a novel Fc-engineered HER2-targeted antibody designed to have greater immune activity. In the preclinical setting, it has demonstrated increased affinity for the IgG CD16A Fc-gamma receptor alleles. It has also demonstrated decreased affinity for inhibitory receptors for IgG Fc gamma.

In the clinical setting, now in a phase III trial, we've seen early evidence that margetuximab may have benefits over trastuzumab in combination with chemotherapy in the third- or greater-line setting. This difference may be due to differential affinity for certain IgG Fc-gamma receptors. We will look for greater data toward the end of the year.

Rugo HS, Im S-A, Wright GLS, et al. SOPHIA primary analysis: a phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol. 2019;37 (suppl; abstr 1000). doi: 10.1200/JCO.2019.37.15_suppl.1000.