On September 22, 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, a journal of the American Society of Hematology (ASH) (Free ASH Whitepaper), which highlights interim results of an ongoing Phase 1/2 clinical trial of flotetuzumab in patients with acute myeloid leukemia (AML) (Press release, MacroGenics, SEP 22, 2020, View Source [SID1234565482]). 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.
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As described in the article titled "Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia," 88 AML patients were enrolled in the Phase 1/2 trial as of November 1, 2019, including 42 in dose escalation and 46 treated with flotetuzumab at the recommended Phase 2 dose (RP2D) of 500ng/kg/day. The majority (56%) had adverse risk by ELN 2017 criteria and 36% had secondary AML. Patients were heavily pretreated, with a median of three lines of prior therapy (range 1-9). Collectively, this group of patients represents a poor-prognosis population having few effective therapies and an otherwise limited life expectancy.
The most common treatment-related adverse event (TRAE) was infusion-related reaction/cytokine release syndrome (IRR/CRS), the majority reported as grade 1-2. Stepwise dosing during week 1, pre-treatment with dexamethasone, prompt use of tocilizumab and temporary dose reductions/interruptions successfully prevented severe IRR/CRS, resulting in acceptable tolerability.
As described in the publication, of 50 evaluable patients with relapsed or refractory AML, 30 patients entered the study with no prior response to induction therapy (primary induction failure AML or PIF AML) or having relapsed within six months of achieving an initial remission (early relapsed AML or ER AML), a combined population with poor prognosis and high unmet medical needs. This PIF/ER AML subset of patients showed a 16.7% (5/30) complete remission (CR) rate and a combined CR and complete remission with partial hematological recovery (CRh) rate of 26.7% (8/30) following flotetuzumab treatment. In contrast, only one of 20 patients with late relapsed AML achieved a CR following flotetuzumab treatment. PIF/ER patients who achieved CR/CRh showed median overall survival (OS) of 10.2 months (range 1.87-27.27), with 6- and 12-month survival rates of 75% (95% CI, 0.450-1.05) and 50% (95% CI, 0.154-0.846).
"The response to flotetuzumab in primary induction failure and early relapsed AML is consistent with our previously published data1 that an IFN-γ-related inflammatory gene expression signature in the AML bone marrow correlated with lack of response to induction chemotherapy but was associated with a greater likelihood to respond 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, and a co-author on the current paper. "AML is a highly heterogeneous disease. Our translational studies provided a strong mechanistic basis for studying flotetuzumab in these AML patients, who currently have few treatment options."
"The results recently published in Blood support our decision to conduct a pivotal study of flotetuzumab in the specific subset of 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. "Moreover, the translational research provides a strong mechanistic basis for studying flotetuzumab in these AML patients, who currently have few treatment options. Our single arm clinical trial is ongoing as an expansion of the Phase 1/2 study, for which we plan to enroll a total of up to 200 patients. We plan to present interim results later this year."
1 "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 experience disease recurrence after a short remission duration (<6 months; early relapsed). 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 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.