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Margetuximab is an Fc-optimized monoclonal antibody that targets the human epidermal growth factor receptor 2, or HER2. HER2 is expressed by tumor cells in breast, gastroesophageal, bladder and other forms of solid tumor cancers, making it a key marker for biologic therapy. Margetuximab is currently being studied as a potential treatment for metastatic breast cancer and gastroesophageal cancer.
MacroGenics is enrolling the SOPHIA study, a Phase 3 clinical trial of margetuximab in patients with metastatic breast cancer. This randomized, multi-center study compares margetuximab plus chemotherapy to trastuzumab plus chemotherapy in subjects with metastatic breast cancer. In January 2018, the Company announced the completion of a pre-planned interim futility analysis with the recommendation of an independent data safety monitoring committee to continue SOPHIA as planned without modification. This analysis was based on a pre-specified assessment of progression-free survival as determined by independent central review. The futility analysis did not allow for early stopping due to efficacy. MacroGenics remains on track to complete enrollment of the 530 patient study by the end of 2018. (Learn More: SOPHIA Study Site).
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.
In January 2018, MacroGenics announced presentation of data from its clinical trial of margetuximab in combination with Merck’s anti-PD-1 therapy, pembrolizumab, for patients with advanced gastric and gastroesophageal junction (GEJ) cancers in a poster session at the 2018 ASCO Gastrointestinal Cancers Symposium.
A Phase 1b dose escalation segment of the study tested dose levels of 10 and 15 mg/kg margetuximab in combination with a flat dose of 200 mg pembrolizumab every three weeks. After completion of dose escalation, Phase 2 dose expansion cohorts were enrolled, including a 30 patient cohort in North America and a 30 patient cohort in Asia. Sixty dose expansion patients received margetuximab at 15 mg/kg and 200 mg of pembrolizumab every three weeks.
Acceptable tolerability was observed in the safety population of 67 patients. Grade 3 or higher treatment-related adverse events (TRAE) occurred in 11.9% of patients. The most common TRAE of any grade was fatigue (14.9%).
As of the December 4, 2017 data cut-off date, responses were evaluable from 51 patients, including 25 with gastric and 26 with GEJ cancer. The Overall Response Rate (ORR) was higher in patients with gastric vs. GEJ cancer (32% vs. 4%). ORR across all patients in the study was 18% (six confirmed and three unconfirmed patients). Similarly, Disease Control Rate (including partial responses and stable disease) was higher in patients with gastric vs. GEJ cancer (72% vs. 38%). Median progression-free survival was also higher in patients with gastric vs. GEJ cancer (5.5 vs. 1.4 months). (Learn More: 2018 ASCO GI Poster).
Based on these results, the Company is expanding the study by enrolling 25 additional gastric cancer patients and will continue to evaluate biomarkers, including HER2 and PD-L1 expression, to determine the patients who are most likely to benefit from margetuximab plus anti-PD-1 therapy.
Data from our Phase 1 study of margetuximab were presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. Margetuximab demonstrated anti-tumor monotherapy activity across several tumor types, including patients with gastric, colorectal and head and neck cancer as well as patients with breast cancer who had received extensive prior therapy and progressed on prior HER2-directed therapy. Tumor reductions were observed in 13 of 19 evaluable patients with breast cancer, including 4 of 19 patients with confirmed partial responses. The most common adverse events (AEs) were Grade 1-2 constitutional symptoms and infusion-related reactions. These data reinforce both the safety profile of margetuximab as well as the rationale for the Phase 3 SOPHIA study. (Learn More – 2015 ASCO Poster)
Using our Fc Optimization platform, we have engineered the Fc region of margetuximab to increase its ability to mediate Fc domain-dependent activities, including enhanced tumor cell killing via antibody-dependent cell-mediated cytotoxicity, or ADCC. Specifically, we increased margetuximab’s ability to bind to activating Fc-gamma receptors and decreased 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. As a result, we believe margetuximab has 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 with Green Cross Corp. on the development and commercialization of margetuximab in South Korea. With the exception of South Korea, MacroGenics retains full worldwide rights to margetuximab.