What Role Now for Margetuximab in HER2 Breast Cancer?

M. Alexander Otto, PA, MMS

November 14, 2022

Final results from a phase 3 trial show no benefit in overall survival (OS) with the newer HER2 inhibitor margetuximab (Margenza) when compared with the older drug trastuzumab in patients with pretreated HER2-positive advanced breast cancer.   

Margetuximab is a HER2 antibody that targets the same epitope as trastuzumab, but it has been modified in such a way to make it more effective, at least in vitro.

The latest finding poses questions about its role in the treatment of this breast cancer patient population.   

The overall survival data come in the final report from the phase 3 SOPHIA trial, which pitted margetuximab against trastuzumab on a background of chemotherapy.

Across 536 subjects, median overall survival with margetuximab was 21.6 months vs 21.9 months with trastuzumab.

The study was published November 4 in the Journal of Clinical Oncology.

Previous results had shown that margetuximab had a progression-free survival (PFS) advantage of almost 1 month over trastuzumab in the initial report from this trial. These data led to the drug’s approval in December 2020.

Now, in the new report, the investigators note that this previously reported PFS improvement “did not translate into a significant difference” in OS.

The investigators were led by Hope Rugo, MD, a breast cancer specialist at the University of California, San Francisco.

They did find a possible OS benefit for margetuximab in patients with a specific CD16A genetic variant, CD16A-158FF, which was present in 38% of the study population. Carriers had a median OS of 23.6 vs 19.2 months with trastuzumab.

However, they also found a possible benefit for trastuzumab in carriers of the CD16A-158VV variant, which was present in 14% of the subjects. Median OS was 31.1 months vs 22 months with margetuximab.

These findings led the investigators to conclude that there still might be room for margetuximab in the breast cancer armamentarium: “Studies in patients with…different CD16A allelic variants are warranted,” Rugo and colleagues said.

An Uncertain Future

Kathy Miller, MD, a breast cancer specialist at Indiana University, Bloomington, was skeptical about the drug in a Medscape commentary after it was approved. The Food and Drug Administration’s approval was based on the PFS improvement seen in the SOPHIA trial, a median of 5.8 months with margetuximab vs 4.9 months with trastuzumab. Although this was statistically significant, “I would argue that the improvement in PFS did not reach clinical significance,” Miller said.

“We’re talking about an improvement in PFS with margetuximab of 20 days to maybe 25 days…in my mind, a 0.9% improvement in PFS is simply not enough. Our patients need more,” she said.

Asked now about her thoughts on the new findings, she said that although there’s “no difference in OS” overall, there might be “a difference in outcome based on genotype, but that is only speculative and would need to be confirmed.”

“The sponsor wants to focus on the genotype that may do better, [but] clinicians should be equally (maybe more) aware of the genotype that may be worse,” Miller said.

Several other oncologists shared their thoughts about the new report on Twitter; many were doubtful about margetuximab’s future.

“With these data” and the higher cost of margetuximab over trastuzumab, “at this time [there is] no real role” for margetuximab in the clinic, commented Bijoy Telivala, MD, from Cancer Specialists of North Florida, Jacksonsville.

Others said, “it’s hard to see how [margetuximab] will survive with so many new HER2 drugs coming on,” and that despite strong theoretical underpinnings, margetuximab just didn’t “pan out in real life.”

Rebecca Shatsky, MD, from the University of California in San Diego, suggested these latest data are the final “nail in the coffin.”

Trial Details

SOPHIA randomized 266 patients to margetuximab and 270 to trastuzumab, both every 3 weeks and on a background of standard, single-agent chemotherapy. Median treatment duration was about 20 months. Subjects had been on trastuzumab beforehand, and over 90% had been on ado-trastuzumab emtansine. All but one had also received pertuzumab. Three hundred eighty-five patients died over a median follow-up of 20.2 months, 194 in the margetuximab and 191 in the trastuzumab arms. There was no difference in survival based on chemotherapy backbone or HER2 status. The toxicity of both drugs was comparable, the investigators said.

The study was funded by MacroGenics, Inc., which makes margetuximab. Four investigators were employees. Other researchers had advisory, research, ownership, and/or other ties to numerous pharmaceutical companies, including MacroGenics. Rugo reported research funding from the company as well as many others, plus consulting for Napo Pharmaceuticals and honoraria from Mylan, Samsung, and others. Miller reported no disclosures.

Journal of Clinical Oncology. Published online November 4, 2022. Full text.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.

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