Initial data of FcRH5/CD3 T-cell-engaging bispecific antibody

Cevostamab is a humanised IgG-based T-cell-engaging bispecific antibody targeting both the most membrane-proximal domain of the Fc receptor-homolog 5 (FcRH5) on myeloma cells and CD3 on T cells. This dual binding facilitates efficient immunological synapse formation, resulting in T-cell activation and potent killing of myeloma cells [1]. Initial clinical activity and safety of cevostamab in relapsed/refractory multiple myeloma (R/R MM) were presented [2].

FcRH5 is a type I membrane protein expressed on B cells and plasma cells. FcRH5 is found on myeloma cells with near 100% prevalence, “making it an attractive target for myeloma immunotherapy,” Dr Adam Cohen (University of Pennsylvania, Philadelphia, USA) stated. GO39775 (NCT03275103) is an ongoing phase 1 trial evaluating the safety, activity, pharmacodynamics, and pharmacokinetics of cevostamab monotherapy in R/R MM patients. Dr Cohen presented dose-escalation data from the single step-up dosing cohort.

Cevostamab was highly active in heavily pretreated R/R MM patients. The overall response rate (ORR) was 53% in patients receiving active doses. Deep and durable responses were observed in patients with high-risk cytogenetics, triple-class refractory disease, and/or prior exposure to anti-CD38 monoclonal antibodies, CAR T cells, or antibody–drug conjugates. The response was irrespective of target expression level in patients assessed to date [2,3].

The safety profile of cevostamab was manageable, 76% had cytokine-release syndrome (CRS), with grade 3 CRS in only 1 patient (2%), and single step-up dosing effectively mitigating the risk for severe CRS [2].

According to Dr Cohen, this data establishes FcRH5 as a novel target in R/R MM and demonstrates the activity of cevostamab monotherapy in this difficult-to-treat patient population. Studies evaluating dose-escalation and dose-expansion are ongoing.

1. Li J, et al. Cancer Cell. 2017;31:383-95.
2. Cohen AD, et al. Initial Clinical Activity and Safety of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma. 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract
3. Nakamura et al. Early Pharmacodynamic Changes in T-Cell Activation, Proliferation, and Cytokine Production Confirm the Mode of Action of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma. 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract 3213.

Posted on 18 February, 202118 February, 2021