Margetuximab Outperforms Trastuzumab in Advanced HER2-Positive Breast Cancer

By Megan Brooks, Reuters Health

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Margetuximab appears to be more effective than trastuzumab, each with chemotherapy, in women with pretreated ERBB2 (formerly HER2)-positive advanced breast cancer, which remains largely incurable, according to initial results of the SOPHIA trial.

Up to one-fifth of all breast cancers are HER2-positive, and identifying new treatment options for patients in the metastatic setting represents a "serious unmet medical need," principal investigator Dr. Hope Rugo, Director of Breast Oncology and Clinical Trials Education, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, said in a news release.

These findings show that margetuximab "provides improvement, for this patient population, beyond what we can achieve with trastuzumab, which is good news for patients with advanced disease," she said.

Margetuximab, from MacroGenics Inc, which funded the trial, is a chimeric antibody that shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation, the study team explains in JAMA Oncology. The drug won regulatory approval in the United States in December 2020.

The SOPHIA phase-3, randomized, open-label trial evaluated margetuximab against trastuzumab, each with chemotherapy, in 536 women with ERBB2-positive advanced breast cancer and disease progression on two or more prior anti-ERBB2 therapies and up to three lines of therapy for metastatic disease.

In the primary analysis of progression-free survival (PFS), performed after 265 PFS events, margetuximab significantly prolonged PFS (median PFS, 5.8 vs. 4.9 months), with a 24% relative risk reduction in the hazard of progression (HR, 0.76; 95% confidence interval, 0.59 to 0.98s), meeting the primary endpoint of the study, report Dr. Rugo and colleagues.

After the second planned interim analysis of 270 deaths, median overall survival was improved with margetuximab (21.6 vs. 19.8 months). The final analysis of overall survival will occur after 385 deaths and is anticipated in 2021.

Margetuximab plus chemotherapy had "acceptable safety, comparable with control trastuzumab plus chemotherapy," the researchers report.

Common adverse events in both groups included fatigue, nausea, diarrhea and neutropenia, as well as vomiting (margetuximab group) and anemia (trastuzumab group). Discontinuations owing to side effects were similar in the margetuximab (3.0%) and trastuzumab groups (2.6%).

Adverse events leading to death were reported in three patients in the margetuximab group and two in the trastuzumab group but none were considered treatment related.

"This trial demonstrates a head-to-head advantage of margetuximab (an Fc-engineered ERBB2-targeted antibody) compared with trastuzumab in a pretreated ERBB2-positive advanced breast cancer population," Dr. Rugo and colleagues conclude in their paper.

"Having another antibody that could work in patients who have a poor response upfront to Herceptin is great and provides us with another line of therapy after patients progress on other treatments," Dr. Rugo told Reuters Health by phone.

Weighing in on the results for Reuters Health, Dr. Amy Tiersten, professor of medicine, hematology and medical oncology at Icahn School of Medicine at Mount Sinai in New York, who wasn’t involved in the trial, said, "Margetuximab now joins the list of several new active agents for the treatment of metastatic Her2neu-positive breast cancer."

"This was a heavily pre-treated group of patients who had progressed after several standard anti-Her2 therapies," she told Reuters Health by email. "It is very exciting to have another unique targeted therapy to add to our armamentarium for the treatment of Her2neu-positive metastatic breast cancer," she added.

The study was funded by MacroGenics, Inc., which sells margetuximab as Margenza. Several authors have financial relationships with the company.

SOURCE: https://bit.ly/2Nqqyga JAMA Oncology, online January 22, 2021.

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