This story has been updated with details about an additional trial in the neoadjuvant setting.
NEW YORK – MacroGenics published results in JAMA Oncology on Friday from the Phase III SOPHIA trial demonstrating the ability of its monoclonal antibody margetuximab (Margenza) plus chemotherapy to extend progression-free survival in metastatic, HER2-positive breast cancer patients compared to trastuzumab (Genentech's Herceptin) plus chemo.
The US Food and Drug Administration relied on the results of the SOPHIA trial to approve margetuximab as a treatment for metastatic HER2-positive breast cancer in December. Patients taking margetuximab plus chemo had a median progression-free survival of 5.8 months, compared to 4.9 months for patients in the trastuzumab and chemo arm. The addition of margetuximab to chemo reduced the risk of progression by 24 percent compared to trastuzumab plus chemo.
"[Margetuximab] is the first HER2-targeted therapy to reduce the risk of disease progression in metastatic breast cancer patients over trastuzumab in a head-to-head comparison involving a heavily pretreated patient population," MacroGenics CEO Scott Koenig said in a statement. "These data represent years of research and clinical development at MacroGenics leading to the forthcoming commercialization of this innovative antibody-based therapeutic for the treatment of metastatic HER2-positive breast cancer."
Researchers are still evaluating margetuximab's impact on median overall survival in the SOPHIA trial. At the second planned interim analysis, when 270 patients had died, median overall survival for patients on margetuximab was 21.6 months versus 19.8 months with trastuzumab. The researchers expect the final overall survival analysis will come in the second half of 2021, after 385 patients have died.
The SOPHIA trial enrolled 536 heavily pretreated patients with metastatic HER2-positive breast cancer. All patients in the trial had been previously treated with two or more anti-HER2 regimens and received between one and three lines of treatment in the metastatic setting. The objective response rate among patients taking margetuximab was 22 percent versus 16 percent in the trastuzumab arm.
Researchers also conducted an exploratory analysis to gauge if patients with certain FCGR genotypes derived differential benefit from margetuximab. Study participants could be optionally tested for CD16A (FCGR3A), CD32A (FCGR2A), and CD32B (FCGR2B) genotypes by PCR. That analysis suggested that patients with the CD16A-158F allele may derive greater progression-free survival benefit with margetuximab than with trastuzumab. The researchers reported that based on early overall survival data they believe this biomarker may also be predictive of overall survival benefit with margetuximab.
"Conversely, there was no margetuximab benefit in the smaller CD16A-158VV group in this study of heavily pretreated patients," the researchers wrote in JAMA Oncology. "There is no clear biological explanation for the observation that margetuximab provided no clinical benefit in CD16A-158VV homozygotes compared with trastuzumab, although there was an imbalance in poor prognostic features between the two groups."
The safety of margetuximab was comparable to trastuzumab in this study. The common adverse events seen in patients due to margetuximab were fatigue, nausea, diarrhea, and vomiting. There was also a higher incidence of infusion-related reactions for patients in the margetuximab arm.
The researchers concluded that there was a "small but statistically significant" progression-free survival benefit for margetuximab over trastuzumab. They also noted that margetuximab could be an alternative to neratinib (Puma Biotechnology's Nerlynx), tucatinib (SeaGen's Tukysa), and trastuzumab deruxtecan (Daiichi Sankyo/Astra Zeneca's Enhertu) for patients who cannot tolerate the toxic effects of those treatments.
The Rockville, Maryland-based company expects margetuximab will be available in the US in March 2021.
Macrogenics is also evaluating margetuximab versus trastuzumab as a neoadjuvant treatment in the Phase II MARGOT study. That trial is studying the drugs in combination with pertuzumab (Genetech's Perjeta) and chemo in early-stage breast cancer patients who are CD16A-158 F carriers. The MARGOT trial is being led by Dana Farber Cancer Institute and the Translational Breast Cancer Research Consortium.