Margetuximab Plus Chemo Reveals Intriguing Benefit in HER2+ Breast Cancer

Hope Rugo, MD

Updated findings of the phase III SOPHIA trial showed that margetuximab plus chemotherapy led to an increase in progression-free survival (PFS) and an overall survival (OS) compared with trastuzumab (Herceptin) plus chemotherapy in patients with HER2-positive metastatic breast cancer who had previously received HER2-targeted therapies, explained Hope S. Rugo, MD, FASCO.

The second interim OS analysis was based off of 270 OS events and showed that, at a median follow-up of 15.6 months, the median OS in the intent-to-treat population was 21.6 months (95% CI, 18.86-24.05) with margetuximab plus chemotherapy versus 19.8 months (95% CI, 17.54-22.28) with trastuzumab plus chemotherapy (HR, 0.89; 95% CI, 0.69-1.13; P = .326). The final prespecified OS analysis is planned after 385 events have occurred, which will likely occur in late 2020.

The investigator-assessed PFS showed a 29% reduction in the risk of disease progression or death with margetuximab compared with the trastuzumab arm. The median PFS for margetuximab/chemotherapy was 5.7 months (95% CI, 5.22-6.97) versus 4.4 months (95% CI, 4.14-5.45) for trastuzumab/chemotherapy (HR, 0.71; 95% CI, 0.58-0.86; P = .0006).

“Overall, the SOPHIA trial showed that margetuximab is safe and similar to trastuzumab and can be given [to patients with HER2-positive breast cancer],” said Rugo, a professor in the Department of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

Based on these data, MacroGenics, Inc, the developer of margetuximab, submitted a biologics license application to the FDA for margetuximab for use in combination with chemotherapy as a treatment for patients with metastatic HER2-positive breast cancer.

In an interview with OncLive^® at the 2019 San Antonio Breast Cancer Symposium (SABCS), Rugo discussed the updated findings of the SOPHIA trial in HER2-positive metastatic breast cancer.

OncLive^®: Could you give an overview of the structure of the SOPHIA trial?

Rugo: SOPHIA is a randomized, phase III, blinded trial evaluating the novel HER2-targeted antibody margetuximab compared with trastuzumab combined with different chemotherapy agents in patients with heavily pretreated HER2-positive metastatic breast cancer. Patients who were enrolled on this trial had received trastuzumab and pertuzumab (Perjeta), and more than 90% had received ado-trastuzumab emtansine (T-DM1; Kadcyla). The primary end points of the trial included PFS by central blinded analysis and OS. Secondary end points included PFS by investigator assessment, safety, and response rate. A really interesting part of the preplanned secondary exploratory end point was to look at variants in the immunoglobulin G (IgG) Fc receptor to see whether there was a differential benefit with margetuximab.

What is the rationale supporting the investigation of margetuximab?

Margetuximab has the same F(ab) fragment as trastuzumab but, as an antibody, the Fc fragment has been altered to enhance immunity. Specifically, margetuximab’s Fc fragment has been engineered to increase affinity for the activating CD16A receptor and decrease affinity for the inhibitory CD32B receptor.

What do the latest findings of the SOPHIA trial show?

At the 2019 SABCS, we presented about 1 year of additional follow-up with PFS by investigator assessment— the central blinded analysis hasn’t happened yet. Margetuximab resulted in a significant improvement in PFS compared with trastuzumab, with a P value that has improved to .0006. It was highly significant and a very good hazard ratio, with a 24% relative improvement. The absolute difference was 1.3 months, which is small, but the P value and hazard ratio are very important in terms of assessing the benefit of margetuximab over trastuzumab. We looked at response and clinical benefit rate, which were significantly increased with margetuximab, and showed a clinically important difference in response.

Then, we looked at a second interim analysis of OS. Now, we have 70% of the planned events and, at this analysis, we see a nonsignificant trend toward improved survival with margetuximab.

We also looked at safety, which was very good with margetuximab. We saw more infusion reactions, but these can be managed. We evaluated a shorter infusion [of the drug] after the first dose and that is very well tolerated.

Then we looked at the impact of the IgG Fc gamma receptor differences on the activity of margetuximab. The CD16A Fc receptor has 2 variants: the F allele and the V allele. The F allele has lower affinity and the V allele has higher affinity. Data have already been shown in which the patients who had the high-affinity allele benefited the most from trastuzumab when trastuzumab was added to chemotherapy—and benefit decreased if you had FV or FF. It’s very interesting.

We hypothesized that patients who carried the F allele would have a better response to margetuximab. In fact, when we looked at OS based on patients who had the F allele, FF or FV, we found a bigger difference in OS. The absolute difference was 4.3 months, which was not yet statistically significant with a P value of .08, but it is very intriguing.

In contrast, when we looked at the patients who are homozygous for V, there were only 69 patients. It turned out that the patients randomized to margetuximab in that group had much worse disease, including more brain metastases, more visceral metastasis, and other poor prognosis features. We found that patients with trastuzumab did better than margetuximab because they were a better-risk group. We concluded that margetuximab has the ability to cause an enhanced immune response through this engineered Fc receptor. We learned that the benefit may be greater in patients who carry the CD16A Fc F allele. No evidence at present suggests that patients who have the V allele benefit from receiving margetuximab over trastuzumab.

What are the next steps of this trial?

These are really very interesting data that suggest that the individual aspects of the patient play a role in how they respond to treatment. We know it’s true for toxicity, and it appears, at least in this situation, that there may be an association with efficacy. The next plan is to wait for the final OS analysis, which we expect at the end of 2020. Also, a neoadjuvant trial is planned that will focus on patients who carry the F variant of the CD16A receptor and that will help us understand whether that group of patients, who have more intact immune systems, benefit more from margetuximab.

Rugo HS, Im S-A, Cardoso F, et al. Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: second interim overall survival analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-02. bit.ly/2N0wKZn.