On December 6, 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 updated results from a single-arm, registrational study of flotetuzumab, an investigational, bispecific CD123 × CD3 DART molecule, in patients with primary induction failure (PIF) and early relapsed (less than six months, or ER6) acute myeloid leukemia (AML) (Press release, MacroGenics, DEC 6, 2020, View Source [SID1234572227]). The data were presented at the 62nd Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) taking place December 5-8, 2020.

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In the open label study of flotetuzumab, 44 AML patients had disease classified as either PIF or ER6. Of these patients, 72.7% (32 of 44) had adverse risk cytogenetics by ELN Risk Stratification (2017). Patients were treated with flotetuzumab at the recommended Phase 2 dose (RP2D) of 500 ng/kg/day by continuous infusion. Data were reported as of the cut-off date of November 10, 2020. The study is currently ongoing, with a total of up to 200 patients planned for enrollment for registrational purposes.

The median time to achieve a response to flotetuzumab was one cycle (range of 1-3 cycles). Responses, including complete remission (CR), CRh (CR with partial hematological recovery) and CRi (CR with incomplete hematological improvement) per a modified International Working Group (IWG) Response Criteria for AML, are summarized in the table below.

PIF/ER (n=44) PIF (n=27) ER6 (n=17)
CR/CRh 25.0% (11) 33.3% (9) 11.8% (2)
CR/CRh/Cri 31.8% (14) 37.0% (10) 23.5% (4)
HSCT 57.1% (8/14) 70.0% (7/10) 25.0% (1/4)
Median Duration of Response 8.13 mos.
(n=14) 15.2 mos.
(n=10) 2.4 mos.
(n=4)
As shown in the table, over 50% of responders (8 of 14) successfully received allogeneic hematopoietic stem cell transplantation (HSCT) as consolidation therapy with durable remission (median not reached). Also, among those PIF/ER6 patients who achieved remission (CR, CRh or CRi), the median duration of response was 8.13 months, with a median overall survival of 10.7 months. Within the PIF/ER6 population, five of ten patients with TP53MUT AML achieved CR/CRh/CRi responses, three of whom went on to receive HSCT. More detailed flotetuzumab clinical data in the TP53MUT AML population is available via a separate poster presentation at ASH (Free ASH Whitepaper) (see "TP53 Abnormalities Correlate with Immune Infiltration and Associate with Response to Flotetuzumab Immunotherapy in Acute Myeloid Leukemia", Session 617).

The most common treatment-related adverse event (TRAE) was infusion-related reaction/cytokine release syndrome (IRR/CRS), which occurred in all patients. However, most CRS events observed were of short duration and mild to moderate (Grade 1 or 2) in severity, with only a single Grade 3 event reported.

"For the approximately 50% of AML patients who fail primary induction therapy or relapse within six months of an initial response, there is no standard of care among the available treatment regimens. Historically, these patients have CR/CRh rates to subsequent interventions in the range of only 5-12% with a median overall survival of approximately 3.5 months. A remission rate of 32% with good duration and a manageable safety profile observed to date in the ongoing registrational study of flotetuzumab in this extremely challenging patient population is very encouraging," said Ibrahim Aldoss, M.D., Assistant Professor of Hematology/HCT at City of Hope Comprehensive Cancer Center.

In addition to the above data provided in an oral presentation, five additional presentations related to flotetuzumab and AML have or will be presented at ASH (Free ASH Whitepaper).

"We are very encouraged by the updated results from this study, and continue to enroll patients in this single arm, registrational trial," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "Especially encouraging is the duration of response we’ve seen to date in this otherwise fragile population of patients for whom no approved therapies exist."

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 ER6). 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.

About Flotetuzumab

Flotetuzumab (previously 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. 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). The FDA has granted orphan drug designation to flotetuzumab for the treatment of AML. MacroGenics retains global development and commercialization rights to flotetuzumab.