Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

Abstract

Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after <6 months (early relapse, ER). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART® antibody-based molecule to CD3ε and CD123. This study reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in adults with relapsed/refractory AML. Eighty-eight AML patients were enrolled, 42 in dose-finding and 46 at the recommended phase 2 dose (RP2D) of 500ng/kg/day. Consistent with flotetuzumab's mode of action, the most frequent adverse events were infusion-related reactions (IRR)/cytokine release syndrome (CRS), the majority as grade 1-2. Stepwise dosing during week 1, pre-treatment dexamethasone, prompt use of tocilizumab and temporary dose reductions/interruptions successfully prevented severe IRR/CRS, resulting in acceptable tolerability. Clinical benefit accrued to PIF/ER AML patients, who showed an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the CR/CRh rate was 26.7%, with an overall response rate (CR/CRh/CRi) of 30.0%. In PIF/ER patients who achieved CR/CRh, median OS was 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). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted complete responses to flotetuzumab (AUROC=0.904 versus 0.672 for the ELN risk classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER AML patients. Trial registration number: NCT02152956.

Emerging agents and regimens for AML

“…Among the primary induction failure/early relapse patients treated at RP2D of 500 ng/kg per day, the CR/CRh rate was 26.7%, and ORR rate was 30.0%. Infusion-related reaction/cytokine release syndrome occurred frequently from 81 to 100% in different cohorts, but grade 3 or above only happened in 3.3-8.0% patients, and was managed with standard supportive care [115]. The outcomes of 38 patients with primary induction failure or early relapse (PIF/ER) treated on the trial was recently presented, the overall complete response rate (CRR) was 42.1% with 68.8% subsequently undergoing allo-SCT.…”

Overcoming Challenges for CD3-Bispecific Antibody Therapy in Solid Tumors

“…Apart from blinatumomab, many other CD3-BsAbs are currently in clinical trials targeting well-established B-cell markers, like CD19, CD20, CD38 and B-cell maturation antigen (BCMA) and myeloid markers, like CD33 and CD123. For instance, in a phase I/II study, patients suffering from acute myeloid leukemia (AML) were treated with flotetuzumab (CD3xCD123 BsAb) and showed promising overall response rates (complete response with full, partial or incomplete recovery of blood cells) of 30% [ 20 ]. In another phase I/II study for patients suffering from diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL) or follicular lymphoma (FL), epcoritamab (CD3xCD20 BsAb) therapy generated impressive responses: 44% complete response (CR) and 11% partial response (PR) for patients with DLBCL or HGBCL and 100% PR for patients with FL [ 21 ].…”

Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors

“…[28][29][30] Diabody-Fcs of this type have shown potent T cell-dependent cytotoxicity and clinical utility. [9][10][11]25 Furthermore, molecules using this format can be produced in a single cell line with a simpler purification process than alternative IgG-like formats we have explored, which require expression of components in two cell lines and subsequent assembly and purification. 31 We identified a panel of anti-GUCY2C hybridomas and determined, by reformatting into diabody format with an anti-CD3 antibody, that a subset of these antibodies supported high-potency T cell-dependent cytotoxicity in vitro (Table S1).…”

“…In this report, we describe the application of a suite of high-throughput technologies to achieve multiparameter optimization of a T-BsAb in the format of a diabody-Fc fusion. [9][10][11] Colorectal cancer (CRC) is among the most frequently diagnosed cancers and a leading cause of cancer deaths worldwide. 12,13 Guanylyl cyclase 2 C (GUCY2C or GCC) belongs to the guanylyl cyclase family of receptors and has been reported to be expressed in several gastrointestinal cancers including more than 90% of CRC across all stages.…”