Treatment with MacroGenics‘ investigational molecule flotetuzumab completely eliminated traces of cancer cells in a large proportion of heavily treated acute myeloid leukemia (AML) patients, data from a Phase 1/2 clinical trial show.
The molecule, made with MacroGenics’ dual affinity re-targeting (DART) platform, is being evaluated in the open-label, dose-expansion trial (NCT02152956) in people with relapsed or refractory AML. The trial is still recruiting for an estimated total enrollment of 179 patients.
Participants were unlikely to benefit from chemotherapy, with fewer than 10% historically achieving remission. After treatment with flotetuzumab, however, about one-third of patients (32.1%) were free of cancer, including 18% who also achieved a complete recovery of blood cells in circulation and in their bone marrow.
These findings were recently presented at the recent American Society of Hematology 2019 Annual Meeting, in an oral presentation, titled “Flotetuzumab, an Investigational CD123 x CD3 Bispecific Dart® Protein, in Salvage Therapy for Primary Refractory and Early Relapsed Acute Myeloid Leukemia (AML) Patients.”
AML patients who fail to achieve complete remission with intensive induction chemotherapy or who relapse less than six months after entering remission are difficult to treat. These patients make up 40% of all newly diagnosed patients, and only 14% will achieve remission with conventional chemotherapy. Subsequent salvage attempts are even less effective.
It is thought that AML arises from a population of leukemic stem cells that are resistant to chemotherapeutic agents and characterized by high levels of the CD123 receptor. In AML, the presence of these CD123-positive leukemia cells is associated with poor prognosis.
Flotetuzumab is an antibody-based molecule that targets both CD123 on leukemia cells and the CD3 receptor on immune T-cells. Its goal is to redirect these immune cells — which have the ability to fight cancer — to kill CD123-positive cells.
In the trial to date, 30 patients with primary refractory AML have received flotetuzumab at the recommended dose, including 24 who failed two or more induction chemotherapy regimens, and six who recurred after a short remission period (median 32 days).
Among the 28 patients eligible for efficacy assessments, a total of 32.1% achieved a complete remission. These included 17.9% of who had a total recovery of blood parameters, or hematological recovery, 10.7% with a partial hematological recovery, and 3.5% with an incomplete hematological recovery.
Four of these patients went on to receive a stem cell transplant and remained in remission after six to 21 months.
“A remission rate of 32% observed in the ongoing study of flotetuzumab in this extremely challenging patient population is noteworthy,” Geoffrey Uy, MD, associate professor, Department of Medicine, Division of Oncology at the Washington University School of Medicine in St. Louis, said in a press release.
“For comparison, the expected [complete remission] rate to conventional salvage therapy in this population was calculated as <10%, estimated based on historical response rates of [patients] subjected to similar numbers and types of salvage therapies,” the researchers said.
Flotetuzumab was generally well tolerated, despite all patients experiencing infusion-related reactions of cytokine release syndrome — a result of excessive immune activation. This condition, however, was mild to moderate in most patients and resolved after a short period.
“Based on the encouraging data from this study, and pending anticipated discussions with the FDA in the first half of 2020, we are planning for a potential registration-enabling study of flotetuzumab in this high unmet need population of patients with refractory AML, who have limited treatment options,” said Scott Koenig, MD, PhD, president and CEO of MacroGenics.
As expected, patients in complete remission had more CD123-positive cells than patients with no response. Additionally, the anti-cancer activity of flotetuzumab was associated with some immune signatures, including higher activity of interferon-gamma (IFNγ), and increased tumor inflammation.
In another oral presentation, “Immune Landscapes Predict Chemotherapy Resistance and Anti-Leukemic Activity of Flotetuzumab, an Investigational CD123×CD3 Bispecific Dart® Molecule, in Patients with Relapsed/Refractory Acute Myeloid Leukemia,” researchers confirmed the findings, showing that IFNγ expression predicts a non-response to induction chemotherapy but is associated with better responses to flotetuzumab.
The team also found that flotetuzumab modifies the tumor microenvironment, increasing immune infiltration into tumors, immune activation, and the levels of the immune checkpoint molecule PD-L1. These findings suggest overall that flotetuzumab may enhance responses to immune checkpoint inhibitors.
MacroGenics is now studying one such combination — flotetuzumab plus its PD-1 inhibitor MGA012 — to confirm the observations.