Session: 622. Lymphomas: Translational – Non-Genetic: Poster II
Hematology Disease Topics & Pathways:
Research, Translational Research, Lymphomas, Non-Hodgkin lymphoma, Diseases, Aggressive lymphoma, Lymphoid Malignancies
NX-5948 is a novel oral small molecule that induces BTK degradation via recruitment of the cereblon E3 ligase complex. NX-5948 is being evaluated for the treatment of B cell malignancies, including patients who have developed resistance to existing BTK inhibitors. NX-5948 induces BTK degradation with subnanomolar potency against both wild-type and mutant forms of BTK in vitro, and demonstrates rapid in vivo degradation in mouse and non-human primate B cells within four hours of oral administration [Noviski et al. iwCLL 2023] [Robbins et al. ASH 2021]. In mice, NX-5948 inhibits the growth of subcutaneously implanted ABC-type DLBCL TMD8 tumors which harbor either wild-type BTK or the ibrutinib-resistant BTK-C481S mutation. In addition, NX-5948 is CNS-penetrant and promotes BTK degradation in microglia and brain-resident lymphoma cells. Previously we demonstrated the pharmacodynamic efficacy of NX-5948 in an intracranial model of secondary CNS lymphoma using SC1 cells derived from a patient with highly refractory CD79B and ETV6-mutant large B-cell lymphoma [Ma et al., Lugano 2023].
Here we evaluated the pharmacodynamic properties of NX-5948 in an intracranial model of PCNSL using PC2 cells derived from a patient with highly refractory MYD88-, CD79B-mutant large B-cell PCNSL that had been treated withhigh-dose methotrexate/rituximab. Upon intracranial implantation, PC2 cells grow aggressively and exhibit diffuse bi-hemispheric brain infiltration in RAG-/- mice, with localization along brain microvasculature as demonstrated by fluorescein labeled Lysopersicon esclutentum staining. A single oral dose of NX-5948 at 90 mg/kg in mice bearing intracranial PC2 tumors yielded 96% degradation of BTK in the tumors. Daily treatment with NX-5948 was associated with marked prolongation of survival in mice with intracranial PC2 tumors (N = 8 mice/cohort) compared to controls, p= 1.2x10-4 (N = 7 mice/cohort) and to mice treated with ibrutinib daily, p = 0.035 (N = 8 mice/cohort). There was no difference in duration of survival between daily treatment with ibrutinib compared to controls. Survival prolongation was further evident following cessation of NX-5948 treatment at 100 days. Four hours after a single oral dose in intracranial tumor-bearing mice, pharmacodynamic analysis demonstrated that ibrutinib and NX-5948 both antagonized ERK phosphorylation in PC2 tumors. By contrast, in vitro chemotaxis studies using OCI-LY10 cells, a cell line model of MYD88-mutant DLBCL, demonstrated that NX-5948 reproducibly antagonized SDF-1 mediated chemotaxis with greater potency compared to ibrutinib. This suggests that the enhanced efficacy of NX-5948 may be due, in part, to anattenuation of tumor invasion in a CNS lymphoma microenvironment. Taken together these preclinical results support the rationale for a phase I study of NX-5948 in relapsed primary and secondary CNS lymphoma (NCT05131022).
Disclosures: Ma: NURIX: Current Employment. Kumar: NURIX: Current Employment. Malla: NURIX: Current Employment. Noviski: NURIX: Current Employment. Rountree: NURIX: Current Employment. Rubenstein: Incyte: Research Funding; Nurix: Research Funding.
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