On October 15, 2020 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported the publication of a manuscript in Blood Advances, a journal of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, MacroGenics, OCT 15, 2020, View Source [SID1234568521]). This represents the third publication of flotetuzumab data in 2020. Flotetuzumab (also known as MGD006), is an investigational, clinical-stage bispecific DART molecule that recognizes both CD123 on leukemic cells and CD3 on T cells, with the intended result of T-cell-mediated killing of leukemic blasts. This most recent publication reports on the role of flotetuzumab in the immunotherapy of TP53-positive acute myeloid leukemia (AML).
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
It has previously been shown1 that an inflammatory (IFN-γ-related) gene expression signature in patients with AML correlated with a lack of response to induction chemotherapy. The same gene signature was shown to be associated with an increased probability of this subset of patients to respond to flotetuzumab. As further described in the article titled "TP53 Abnormalities Correlate with Immune Infiltration and Associate with Response to Flotetuzumab Immunotherapy in AML," AML with TP53 abnormalities was also associated with immune infiltration in the tumor microenvironment (TME); moreover, patients with TP53 abnormalities derived benefit from flotetuzumab immunotherapy.
"Previous translational studies demonstrated that patients who failed to respond to induction therapy (primary induction failure, or PIF, AML) or those who relapsed within six months of achieving an initial remission (early relapsed, or ER, AML) had an immune-infiltrated TME that not only associated with resistance to standard-of-care chemotherapy regimens, but also with response to flotetuzumab," said Sergio Rutella, M.D., Ph.D., FRCPath, John van Geest Cancer Research Centre, College of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom. "Included in this PIF/ER AML population are patients harboring TP53 abnormalities, a particularly difficult to treat subset of AML associated with poor prognosis. Interestingly, these patients who responded poorly when treated with standard-of-care chemotherapy regimens appeared to benefit from flotetuzumab therapy."
"The results published today in Blood Advances, combined with data from previous articles published in Blood and Science Translational Medicine, further support our decision to conduct a pivotal study of flotetuzumab in AML patients who have previously experienced either a primary induction failure or an early relapse when treated with standard-of-care chemotherapy regimens. These individuals represent approximately 40-50% of all AML patients," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "Our single arm clinical trial is ongoing as an expansion of the Phase 1/2 study, for which we plan to enroll up to 200 patients. We plan to present interim results at a medical conference later this year."
1 "Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia," Blood, 2020; and "Immune Landscapes Predict Chemotherapy Resistance and Immunotherapy Response in Acute Myeloid Leukemia," Science Translational Medicine, 2020.
About Acute Myeloid Leukemia
AML is a hematological malignancy characterized by differentiation arrest and uncontrolled clonal proliferation of neoplastic precursors that prevent normal bone marrow hematopoiesis. Nearly 20,000 new cases of AML are diagnosed in the U.S. each year, with a median age of 69 years at diagnosis. Approximately 40-50% of newly diagnosed patients fail to achieve a complete remission with intensive induction therapy (primary induction failure, or PIF) or experience disease recurrence after a short remission duration (<6 months; early relapsed, or ER). A very small number of these patients are expected to respond to salvage therapy. Although new targeted agents have been approved for the treatment of frontline or relapsed/refractory AML in recent years, approximately 50% of patients have no known targetable mutations. The discovery by the Rutella lab of an immunological gene signature in the AML tumor microenvironment forms the basis for a potential predictive biomarker for further clinical validation.
About Flotetuzumab
Flotetuzumab (also known as MGD006) is a clinical-stage bispecific, investigational DART molecule that recognizes both CD123 and CD3. CD123, the interleukin-3 receptor alpha chain, has been reported to be over-expressed on malignant cells in AML and other hematologic malignancies. The primary mechanism of action of flotetuzumab is believed to be its ability to redirect T lymphocytes to kill CD123-expressing cells. To achieve this, the DART molecule combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123 on the target cells. Data from the Phase 1/2 clinical study of flotetuzumab in patients with primary induction failure / early relapse (PIF/ER) AML were presented in December 2019 at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. MacroGenics is conducting a single-arm, registration-enabling clinical study to evaluate flotetuzumab in up to 200 patients with PIF/ER AML, with complete remission (CR) and CR with partial hematological recovery (CRh) as the primary endpoint. The study will be conducted as a continuation of the ongoing Phase 1/2 study (NCT02152956; to be updated). The FDA has granted orphan drug designation to flotetuzumab for the treatment of AML. (Press release, MacroGenics, OCT 15, 2020, View Source [SID1234568521])