The Food and Drug Administration approved the HER2-targeted therapy margetuximab (Margenza) to be given with chemotherapy to treat metastatic, HER2-positive breast cancers after progression despite treatment with two or more other targeted therapies. The approval was announced in December 2020 by MacroGenics, the makers of margetuximab.

The approval was based on the phase III SOPHIA trial, which was presented at the 2019 ASCO Annual Meeting. The trial showed people given margetuximab and chemotherapy went longer without cancer growing compared to people given trastuzumab (Herceptin or biosimilar) and chemotherapy. But with a difference of less than 1 month between the margetuximab and trastuzumab groups and no significant effect yet seen on overall survival, people living with HER2-positive metastatic breast cancer have questioned if the medicine earned its FDA approval.

Background

Margetuximab is a monoclonal antibody that targets the HER2 protein that is overexpressed in HER2-positive breast cancers. It is given by vein in combination with chemotherapy.

In the phase III SOPHIA trial, 536 people with metastatic, HER2-positive breast cancer were randomly assigned to one of two treatment groups:

• Margetuximab and chemotherapy
• Trastuzumab and chemotherapy

Everyone in the group had been treated with at least two lines of targeted therapy in the past, at least one of which had been for metastatic disease. All participants had previously been treated with trastuzumab, and all but one participant had been treated with pertuzumab (Perjeta). Over 90 percent of the participants in each group had also been treated with ado-trastuzumab emtansine (Kadcyla).

The main interests of the researchers are progression-free survival, how long people went without the cancer growing, and overall survival, how likely people were to die of any cause. The study found that the margetuximab group had longer progression-free survival than people in the trastuzumab group. People went without cancer growing for

• 5.8 months when given margetuximab and chemotherapy
• 4.9 months when given trastuzumab and chemotherapy

The difference was statistically significant, meaning it is very unlikely to be the result of chance. The study also found that margetuximab resulted in a higher objective response rate, meaning that more people had the cancer shrink while being given margetuximab compared to the group given trastuzumab. The objective response rates were

• 22.1 percent in the margetuximab group
• 16.0 percent in the trastuzumab group

At the time of the approval, researchers have not reported a statistically significant difference in overall survival.

The most common side effects of margetuximab were fatigue, nausea, neutropenia, and diarrhea. The rates at which people experienced side effects were mostly similar to the trastuzumab group, but people given margetuximab were more likely to have a reaction to the infusion, when the medicine is actually given:

• 12.9 percent of people given margetuximab had an infusion-related reaction.
• 3.8 percent of people given trastuzumab had an infusion-related reaction.

Researchers note that the reactions were mostly minor and are managed with medicine given before coming in for future infusions.

MacroGenics expects margetuximab to be available for use starting in March 2021.

What this means for you

Margetuximab is the fourth medicine approved by the FDA in just over a year to treat metastatic, HER2-positive breast cancer after standard targeted therapy. Trastuzumab deruxtecan (Enhertu) was approved in this setting in December 2019. Tucatinib (Tukysa) and neratinib (Nerlynx) were approved as part of combination treatments in early 2020. Neratinib was approved to be given with the chemotherapy pill capecitabine (Xeloda), and tucatinib was approved to be given with both trastuzumab and capecitabine.

Patient advocates have expressed concern online with the FDA approval of margetuximab based on what is seen as an unusually slight improvement in progression-free survival: the margetuximab group went less than a month longer than the trastuzumab group without cancer growing, and the study has not yet found if margetuximab leads to longer overall survival.

Having these new options available for treatment, especially treatments that have proven to work after other medicines have stopped working, is good news. Future studies will look at margetuximab in different situations and in combination with other medicines to find if there are uses where it is more effective.