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

Introduction: Fc receptor-homolog 5 (FcRH5) is an immunoglobulin (Ig) domain-containing type I membrane protein that is expressed exclusively in the B-cell lineage. FcRH5 expression is retained in myeloma cells, with near 100% prevalence, and is elevated vs normal B cells. BFCR4350A is a humanized IgG-based T-cell-engaging bispecific antibody. Binding of BFCR4350A to the most membrane-proximal domain of FcRH5 on myeloma cells and to cluster of differentiation 3 (CD3) on T cells results in efficient immunological synapse formation and potent T-cell-directed killing of myeloma cells (Li, et al. Cancer Cell 2017). An ongoing Phase I dose-escalation study (GO39775; NCT03275103) is investigating the safety, activity, pharmacodynamics (PD) and pharmacokinetics of BFCR4350A monotherapy in patients (pts) with relapsed/refractory (R/R) multiple myeloma (MM). In Arm A, clinical activity was observed at the 3.6mg/20mg (step/target) dose level and above, and toxicity was manageable (Cohen, et al. ASH 2020). We present preliminary biomarker data that demonstrate the mode of action (MOA) of BFCR4350A, provide support for Cycle (C) 1 step-up dosing, and offer preliminary insights into markers that may predict response.

Methods: In Arm A, R/R MM pts receive BFCR4350A by intravenous infusion in 21-day cycles. In C1, a single step-up dosing approach is used to mitigate the risk for cytokine release syndrome (CRS), with the step dose given on C1 Day (D) 1 and the target dose given on C1D8. The target dose is then administered on D1 of each subsequent cycle. PD changes in peripheral blood (PB) are assessed at baseline and at multiple time points within C1 by whole blood flow cytometry, plasma cytokine electrochemiluminescence and digital ELISA. Tumor biomarkers are assessed at baseline and pre-C2 by bone marrow (BM) biopsy dual CD138/CD8 immunohistochemistry staining and BM aspirate flow cytometry. The clinical cut-off date used for the current analyses was April 13, 2020.

Results: At cut-off, all pts in Arm A (n=51) were biomarker evaluable. FcRH5 expression on myeloma cells was detected in all pts. Dose-dependent PD changes in PB were observed 24-192 hrs after the C1D1 infusion. Variable reduction in circulating T cells was observed 24 hrs after the 0.3-1.8mg C1D1 doses, while consistent reduction was observed after the 3.6mg C1D1 dose, with recovery by C1D8 (192 hrs). T-cell activation was detected 24 hrs post-infusion by upregulation of CD69 in CD8 and CD4 T cells and elevation of IFN-γ in plasma (median increase of ~150-fold from baseline), while T-cell proliferation (Ki67+) peaked by C1D8. At the 3.6mg C1D1 dose, CD8 T-cell activation and proliferation were up to 20-fold higher than at baseline. Minimal elevation of IL-6 was observed post-infusion in pts who received doses below 3.6mg on C1D1, while more consistent increases (≥100pg/ml) were observed in pts who received 3.6mg. IL-6 levels peaked within 24 hrs of the C1D1 dose and the kinetics of IL-6 increase were associated with dose and risk for CRS. Step-up dosing mitigated the risk for severe CRS, as evidenced by lower IL-6 levels after the C1D8 target dose compared to the 3.6mg C1D1 step dose in 27/33 (82%) pts (see Cohen, et al. ASH 2020 for corresponding clinical data). Preliminary data suggest that pts who respond to BFCR4350A have more pronounced T-cell expansion in PB, irrespective of baseline CD8 T-cell levels during the first week of C1. Analysis of the subset of pts with paired BM biopsies (n=19 pts) revealed that levels of CD8+ tumor infiltrating T-cells (TILs) were higher in responding pts than in non-responding pts at the end of C1.

Conclusions: In this study, we demonstrated that early PD changes in T-cell activation, proliferation, and cytokine production confirm the MOA of BFCR4350A and support C1 step-up dosing for CRS mitigation in R/R MM. Early data suggest that at the end of C1, higher peripheral CD8 T-cell expansion and TILs are observed in responding pts than in non-responding pts. Additional analyses are ongoing to establish BFCR4350A response predictors and to better characterize the populations that are likely to benefit. Updated data will be presented.