December 18, 2020
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Catalyst Info & Data Links
TITLE: Margetuximab in HER2-positive metastatic breast cancer - PDUFA
ClinicalTrial.gov (Margetuximab in Breast cancer)
WHAT IS THE CATALYST EVENT?
WHEN WILL THE EVENT (OR DID THE EVENT) OCCUR?
December 18, 2020 (see slide 5)
ASCO 2020 - SOPHIA Analysis by Chemotherapy (Ctx) Choice: A Phase 3 (P3) Study of Margetuximab (M) + Ctx vs Trastuzumab (T) + Ctx in Patients (pts) with Pretreated HER2+ Metastatic (met) Breast Cancer (MBC)
SABCS 2019 - Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: second interim overall survival analysis
SABCS 2019 - Phase 3 SOPHIA Study of Margetuximab + Chemotherapy vs Trastuzumab + Chemotherapy in Patients With HER2+ Metastatic Breast Cancer After Prior Anti-HER2 Therapies: Infusion Time Substudy Results
ESMO 2019 - Evaluation of Tumor Microenvironment Identifies Immune Correlates of Response to Combination Immunotherapy with Margetuximab (M) and Pembrolizumab (P) in HER2+ Gastroesophageal Adenocarcinoma (GEA)
2020: Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22–05): a single-arm, phase 1b–2 trial. The Lancet Oncology, 21(8), 1066-1076.
2017: First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann Oncol. 2017 Apr 1;28(4):855-861
2011: Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fc-gamma receptor binding properties. Breast Cancer Research, 2011 November 30;13:R123.
MECHANISM OF ACTION / RATIONALE
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.
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:
Modulation of HER2 signaling, resulting in growth retardation or the induction of apoptosis, or cell death;
ADCC and improved binding to immune cells to enhance destruction of HER2+ tumor cells; and
Presentation of tumor antigens by cells such as macrophages that take up and display the antigens to other cells of the immune system, including T cells.
Updated by HC
MGNX, Margetuximab, cancer, oncology, breast cancer, cancer, breast, HER2, metastatic
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