Robust Bruton’s tyrosine kinase (BTK) degradation with NX‐5948, an oral BTK degrader, in a first‐in‐human phase 1a trial in relapsed/refractory B cell malignancies

Introduction: Although BTK inhibitors are widely used for treating B cell malignancies, acquired resistance mutations represent a growing clinical challenge. NX-5948 is novel oral small molecule that induces degradation via recruitment of the cereblon E3 ligase complex. being evaluated as treatment tumors with to or in indications where less effective. sub-nanomolar potency wild-type and mutant vitro, demonstrating rapid vivo mouse non-human primate cells within 2 h administration. crosses blood-brain barrier degrades intracranially, translating preclinical efficacy brain lymphoma disease models. Here we report preliminary PK/PD findings from phase 1a trial malignancies. Methods: NX-5948-301 first-in-human, dose-escalation (phase 1a) cohort-expansion 1b) study designed evaluate safety, tolerability, activity relapsed/refractory malignancies (NCT05131022). Phase will safety tolerability patients (pts) CLL, SLL, non-GCB DLBCL, FL, MCL, MZL, WM, including those secondary CNS involvement any indication plus PCNSL. Key eligibility criteria: ≥2 prior lines therapy; measurable other evaluable per specific response criteria; ECOG PS 0–1. given orally, once daily, dose escalation (3+3 design). Approximately 110 pts (30 1a, 80 may be enrolled treated until confirmed progression unacceptable toxicity. Pharmacokinetic parameters generated using non-compartmental analysis. Pharmacodynamic biomarkers assessed whole blood longitudinally 10-color flow cytometry assay quantify BTK. Results: As Dec 1, 2022, 7 have been received at 50 mg (n = 4) 100 3). Baseline demographics/disease characteristics: median age 59.0 (range 46.0–79.0) years; male/female 57.1%/42.9%; white 100%; 0/1 42.9%/57.1%; time since diagnosis 7.6 2.9–23.5) years. Primary diagnosis: DLBCL 2), MCL MZL FL 1). Most 6) ≥4 therapy. exhibited dose-proportional PK, half-life ∼12 h, Tmax 2–3 h. Rapid, robust sustained was observed all dosed, regardless their absolute starting level, tumor type, level NX-5948. Encore Abstract - previously submitted EHA 2023 The research funded by: Nurix Therapeutics Inc. Keyword: Molecular Targeted Therapies Conflicts interests pertinent abstract. F. Forconi Consultant advisory role: BC platform Honoraria: Abbvie, Janssen-cilag, Beigene, Astra-Zeneca Educational grants: Janssen-Cilag, Beigene Other remuneration: Speakers bureau: Astra-Zeneca; Private Clinical Activity: Southampton General Hospital Solent Suite J. Riches Janssen M. Gleeson Speaker fees: Incyte S. G. Injac Employment leadership position: Stock ownership: Nandakumar Tan Cherala