Margetuximab outperformed trastuzumab in a phase III, head-to-head trial of the two anti-HER2 agents among patients with HER2-positive metastatic breast cancer. The new antibody drug was engineered for enhanced immune activity against HER2-expressing tumor cells.

An experimental antibody that works much like the anti-HER2 agent trastuzumab (Herceptin; Genentech), but with stronger induction of antitumor immunity, offered a modest benefit for patients with relapsed HER2-positive breast cancer who had received at least two prior therapies.

That's according to a primary analysis of the 536-patient phase III SOPHIA trial, presented by Hope Rugo, MD, of the University of California, San Francisco, on June 4 at the 2019 American Society of Clinical Oncology Annual Meeting in Chicago, IL.

The trial compared trastuzumab with margetuximab (MacroGenics), an Fc-optimized antibody that binds the same HER2 domain as trastuzumab but with elevated affinity for the CD16A receptor on natural killer cells, which triggers antibody-dependent cell-mediated cytotoxicity (ADCC) against tumors. Margetuximab also has decreased affinity for the inhibitory receptor CD32B.

In the trial, patients with HER2-positive metastatic breast tumors who received chemotherapy plus margetuximab after treatment with both trastuzumab and pertuzumab (Perjeta; Genentech) and at least one other therapy had a higher response rate than those who received chemotherapy and trastuzumab again, as is common practice today. Overall response rates were 22% and 16%, respectively.

Median progression-free survival (PFS) was also longer with the investigational drug—5.8 months versus 4.9 months—while safety profiles were comparable between the two therapies. Overall survival data were not yet available.

Dubbed “super trastuzumab” because of its immune-enhanced activity against HER2-positive tumor cells, margetuximab had the most pronounced benefit among patients with the common low-affinity CD16A-158F allele, which does not engage the Fc domain of trastuzumab well. In this subgroup, median PFS was 6.9 months and 5.1 months, respectively, with the greatest benefit seen in patients homozygous for this allele.

The clinical finding dovetails with earlier laboratory results showing larger differences in ADCC potential between margetuximab and trastuzumab in effector cells isolated from donors who harbor the low-binding allele. However, “it's a little controversial how much ADCC plays a role” in the tumor-killing action of anti-HER2 antibodies, says Sara Hurvitz, MD, of the University of California, Los Angeles, Jonsson Comprehensive Cancer Center.

By binding HER2 and negatively affecting its receptor function, both margetuximab and trastuzumab also likely exert an apoptotic signal on cancer cells. Hurvitz, who was a site investigator in the SOPHIA trial, acknowledges that the difference in patient outcomes on the two anti-HER2 agents suggests that ADCC “does appear to matter, but does it matter in a huge way?” she asks. “The debate continues.”

Based on the results, MacroGenics announced plans to file for regulatory approval with the FDA later this year. If approved, the drug could have worldwide sales of $280 million to $650 million a year for previously treated HER2-positive metastatic breast cancer, analysts predict. In comparison, trastuzumab generated global revenues of more than $7 billion last year, although that number is expected to plummet with four trastuzumab biosimilars already approved by the FDA and others in development.

MacroGenics is also evaluating margetuximab in combination with the checkpoint inhibitor pembrolizumab (Keytruda; Merck) for the treatment of HER2-positive esophageal and gastric cancers. Plus, the company has another Fc-optimized drug—the B7-H3–targeted agent enoblituzumab—in development for head and neck cancer. –Elie Dolgin