MacroGenics presented new, phase 3 breast cancer data from its HER2-targeting antibody margetuximab as it works to put the finishing touches on the drug’s approval application to the FDA in the final weeks of this year.
The company announced that margetuximab’s SOPHIA trial met its first in a series of sequential primary endpoints in February: The antibody outperformed Herceptin head to head, with each combined with one of four chemotherapies, by improving progression-free survival in HER2-positive metastatic breast cancer patients.
Now, in an exhibition at the San Antonio Breast Cancer Symposium, MacroGenics delivered its second interim analysis with an evaluation of the drug’s effect on overall survival (OS). The numbers again favored margetuximab, with a median OS of 21.6 months versus Herceptin’s 19.8, though with p-value of 0.326 the results were not statistically significant.
An exploratory analysis of participants carrying a specific genotype of CD16A—a receptor molecule found on the surface of different immune cells—saw a larger difference in median OS, of 4.3 months. Although with a p-value of 0.087, this was shy of statistical significance as well.
However, CD16A genotypes with a 158F allele, a single amino acid difference, are seen in about 85% of the drug’s intended population—that is, late-stage patients who have already progressed through multiple HER2-targeting therapies including Herceptin, Perjeta and Kadcyla. This biomarker has also been associated with poor responses to Herceptin in the past, according to MacroGenics CEO Scott Koenig.
“We designed the margetuximab molecule so that it would better engage this receptor—with this form, and this sequence variation—and as a result the magnitude of effectiveness went up quite dramatically,” Koenig told FierceBiotech.
At its heart, Margetuximab is essentially a bispecific molecule. While the pronged top half of the Y-shaped antibody similarly binds to HER2 with the same specificity and affinity as Herceptin, its bottom tail, or Fc region, is designed to have a higher affinity for activating immune cells’ CD16 receptors.
"This is the first time that anybody has done head-to-head testing of an antibody molecule based on this Fc variation in this receptor, and showed superiority compared to a so-called wild-type antibody," Koenig said. "This includes other tumor types as well."
Margetuximab is also being studied in metastatic gastric cancer, in combination with an anti-PD1 treatment. MacroGenics’ phase 2/3 MAHOGANY study in front-line patients recently began enrolling patients, with the company eyeing an accelerated approval submission if all goes well.
In the SOPHIA trial, what did achieve statistical significance was the investigator PFS analysis—in new data gathered up to a September 2019 cutoff—showing a 29% risk reduction with margetuximab compared to Herceptin (p=0.0006).
“What's even more impressive is the fact that it's working in patients who've been sort of beaten up through their various chemotherapeutic treatments, which impair the natural immune system,” he added. “The fact that these patients' immune systems can be harnessed to be more effective is a great advance here.”
Additionally, MacroGenics expects to see margetuximab perform even better in earlier lines of therapy, where patients may have stronger immune systems. The company is planning a study of the antibody in the neo-adjuvant setting.
But before that, MacroGenics hopes to submit its biologics license application—the company’s first—to the FDA imminently, by Dec. 31. The agency previously granted margetuximab a fast-track designation. The SOPHIA trial’s final OS analysis is expected in late 2020.