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Margetuximab is an investigational monoclonal antibody that targets HER2-expressing tumors, including certain types of breast and gastroesophageal cancers. HER2 is critical for the growth of many types of tumors. Using MacroGenics’ Fc Optimization platform, the constant region (Fc region) of margetuximab was engineered to increase its ability to kill tumor cells through an Fc-dependent mechanism, including antibody dependent cell-mediated cytotoxicity (ADCC). Margetuximab is currently being studied as a potential treatment for HER2-positive metastatic breast cancer and advanced gastric cancer.
Margetuximab is being evaluated in SOPHIA, a Phase 3 clinical trial of margetuximab in patients with HER2-positive metastatic breast cancer. The study met its first sequential primary endpoint of progression-free survival (PFS). The median PFS of patients treated with margetuximab and chemotherapy was 5.8 months compared to 4.9 months in patients treated with trastuzumab and chemotherapy (hazard ratio [HR]=0.76; 95% CI: 0.59-0.98; P=0.033). Among the approximately 85% of patients carrying the CD16A 158F allele, a pre-specified exploratory subpopulation in the study, PFS was prolonged by 1.8 months in the margetuximab arm compared to the trastuzumab arm (6.9 months versus 5.1 months; HR=0.68; 95% CI: 0.52-0.90; P=0.005). The objective response rate (ORR), a secondary outcome measure in the SOPHIA study, was 22% in the margetuximab arm (95% CI: 17.3-27.7%) compared to 16% in the trastuzumab arm (95% CI: 11.8-21.0%). The data cut-off date for the primary PFS analysis of the study was October 10, 2018.
At the time of the primary PFS analysis, overall survival (OS) data based on 158 events were immature. The median OS at that time was prolonged by 1.7 months in patients treated with margetuximab and chemotherapy compared to patients treated with trastuzumab and chemotherapy. For the exploratory subpopulation of patients carrying the CD16A 158F allele, the median OS was prolonged by 6.8 months in the margetuximab arm compared to the trastuzumab arm. The Company anticipates conducting a second pre-specified interim OS analysis based on 270 events in the second half of this year. The final pre-specified OS analysis is planned after 385 events have accrued, and is projected to be completed in 2020.
The SOPHIA study enrolled 536 patients at approximately 200 trial sites across North America, Europe and Asia. The study evaluated margetuximab in a Phase 3 clinical trial in patients with advanced HER2-positive breast cancer who had received at least two prior lines of anti-HER2-directed therapy in the metastatic setting, or in the case of having received (neo)adjuvant pertuzumab, at least one prior line of anti-HER2-directed therapy in the metastatic setting, and who have received at least one and no more than three prior lines of therapy overall in the metastatic setting. Patients were treated with either margetuximab or trastuzumab in combination with one of four chemotherapy agents (capecitabine, eribulin, gemcitabine or vinorelbine). All study patients had previously received trastuzumab and pertuzumab, and approximately 90% had previously received ado-trastuzumab emtansine. The combination of margetuximab and chemotherapy demonstrated acceptable safety and tolerability, comparable overall to that of trastuzumab and chemotherapy.
Margetuximab with chemotherapy had an acceptable safety profile, generally comparable overall to that of trastuzumab and chemotherapy. Grade 3 or greater adverse events occurred in 138 (52%) patients on the margetuximab arm compared to 128 (48%) patients on the trastuzumab arm. Serious adverse events occurred in 39 (15%) patients on the margetuximab arm compared to 46 (17%) patients on the trastuzumab arm. Infusion-related reactions were more common with margetuximab treatment than with trastuzumab (13% versus 4%) and were mostly Grade 1 or 2 and associated with the first dose.
These results were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in June 2019.
The U.S. FDA has granted Fast Track designation for the investigation of margetuximab for treatment of patients with metastatic or locally advanced HER2 positive breast cancer who have previously been treated with anti-HER2-targeted therapy.
Margetuximab is being evaluated in a Phase 2 clinical trial in patients with HER2-positive gastric or gastroesophageal junction cancer in combination with an anti-PD-1 monoclonal antibody. The Phase 2 clinical trial seeks to characterize the safety, tolerability, maximum tolerated dose, and antitumor activity of this combination. Enrolled patients had relapsed or refractory advanced HER2-positive gastric or gastroesophageal junction cancer with disease progression after or resistance to treatment with trastuzumab plus chemotherapy. The 25 patients in the most recently enrolled expansion cohort had HER2-positive gastric carcinoma that was 3+ by immunohistochemistry. Patients in the study were enrolled irrespective of programmed death ligand 1 (PD-L1) expression status.
As of a January 8, 2019 data cut-off date, objective responses were observed in 18 of 55 HER2-positive (as indicated by a 3+ score on an immunohistochemistry test) response-evaluable gastric cancer patients, including 14 confirmed and 4 unconfirmed. The objective response rate (ORR) for this population was 32.7%, with a disease control rate (DCR) (which includes partial responses and stable disease) of 69.1%. Median PFS was 4.7 months. In the subset of these patients who were also PD-L1 positive, objective responses were observed in 12 of 23 (52.2%) patients, with a DCR of 82.6% and PFS of 4.14 months. As of the data cut-off date, the study was ongoing with 13 gastric cancer patients remaining on therapy. The median OS had not been reached in either of these groups. Acceptable tolerability was observed in the safety population of 95 patients, 92 of whom were treated at the recommended Phase 2 dose of 15 mg/kg for margetuximab and 200mg for the anti-PD-1 monoclonal antibody, both on an every three week schedule of administration. Grade 3 or higher treatment-related adverse events occurred in 17.9% of patients, the most common of which was infusion-related reaction (3.2%).
These data were presented at the ASCO GI Cancers Symposium in January 2019.
Using MacroGenics’ Fc Optimization platform, the constant region (Fc region) of margetuximab was engineered to increase its ability to kill tumor cells through an Fc-dependent mechanism, including ADCC. Specifically, margetuximab’s ability to bind to activating Fc-gamma receptors was increased and its ability to bind to the Fc-gamma inhibitory receptor on immune effector cells, including monocytes, macrophages, dendritic cells and natural killer, or NK, cells, was decreased. As a result, margetuximab may have the potential to be effective in a broader population than is currently treated with trastuzumab and may overcome resistance in populations that no longer respond to trastuzumab. (Learn More: Fc Optimization Platform)
Margetuximab is believed to mediate its therapeutic activity against HER2+ tumors by a combination of mechanisms including:
MacroGenics is collaborating on the development and commercialization of margetuximab with Green Cross Corp. in South Korea and Zai Lab in Greater China. MacroGenics retains full development and commercialization rights in all other territories.