Description
Abstract Type: Oral PresentationSession Title: Novel therapies in relapsed and refractory CLL and hairy cell leukemia
Background: Emerging BTK inhibitor (BTKi)-resistance mutations along with the newly described kinase-independents caffolding function of BTK present a need for approaches beyond BTKi for the treatment of B-cell malignancies. NX-5948 is a novel, orally administered, small molecule that induces specific degradation of both wild-type and mutant forms of BTK in B-cells by the cereblon E3 ligase complex. In addition, NX-5948 can cross the blood-brain barrier, translating into preclinical efficacy in murine CNS lymphoma models.
Aims: Here we report updated safety and efficacy findings from a Phase 1a trial of NX-5948 in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL), including pts with CNS involvement.Methods:NX-5948-301 is a Phase 1, first-in-human dose-escalation trial evaluating safety, tolerability, and clinical activity of NX-5948 in pts with R/R CLL and NHL in parallel 3+3 dose-escalation cohorts followed by dose-expansion cohorts. Key eligibility criteria include: ≥2 prior therapy lines; measurable or other evaluable disease per indication-specific response criteria; ECOG PS 0–1. Primary objective: evaluate safety and tolerability of NX-5948 and establish maximum tolerated dose and recommended Phase 2 dose.
Key secondary objectives: characterize PK/PD profile and assess preliminary efficacy of NX-5948.
Results: As of 16 Jan 2024, 46 pts (16 CLL, 30 NHL of which 6 had CNS involvement) were enrolled at 6 daily oral dose levels: 50 mg (n=7), 100 mg (n=8), 200 mg (n=9), 300 mg (n=12), 450 mg (n=6), 600 mg (n=4). Median age was 64 (range 42–88) years and 67.4% were male; median prior lines of therapy: 4 (range 2–14), including for CLL: BCL2i + covalent/non-covalent BTKi (n=14/16), PI3Ki (n=5/16); for NHL: covalent/non-covalent BTKi(n=19/30), bispecific antibody (n=6/30), CAR-T (n=9/30). Baseline mutations were present in a sizeable number of pts with CLL: BTK (n=5/12), TP53 (n=5/12), PLCg2 (n=2/12). In the overall population (n=46),median duration of follow-up was 3.4 (range 0.2–20.1) months. NX-5948 was well tolerated across all doses with no treatment-related SAEs and no discontinuations due to TEAEs. The most common TEAEs were purpura/contusion (39.1%, no Grade ≥3), thrombocytopenia (37.0%, 10.9% Grade ≥3), neutropenia (26.1%,19.6% Grade ≥3). No atrial fibrillation/flutter was reported. A single DLT was observed in the 450 mg (DLBCL)backfill cohort (non-protocol-mandated dose hold due to rash; did not recur with rechallenge). NX-5948 PK supported once-daily dosing. Rapid, robust, and sustained BTK degradation was observed in all pts regardless of absolute BTK starting level, tumor type, or dose. In CLL, out of 10 disease-evaluable pts, 7 PRs were observed at doses of 50–200 mg (ORR 70%; see figure). In NHL, out of 24 disease-evaluable pts treated with 50–600 mgNX-5948, 8 pts responded. All 4 pts treated at the 450 mg dose achieved response: 3 CRs (MCL, MZL, primary CNS lymphoma); 1 PR (secondary CNS lymphoma).
Summary/Conclusion:
Preliminary findings from this ongoing first-in-human study of NX-5948 demonstrate a tolerable safety profile
across B-cell malignancies. Deep clinical responses were observed in a heavily pre-treated population of pts with CLL and NHL, some with BTKi resistance mutations, high-risk molecular features, and CNS involvement. These data suggest a role for NX-5948 in the CLL treatment landscape and warrant its continued investigation in NHL, including subtypes where BTKi may not be sufficient. Additional data at higher dose levels and longer treatment durations will be presented.
| Period | 2024 |
|---|---|
| Event title | European Hematology Association (EHA) Hybrid Congress 2024 |
| Event type | Conference |
| Location | Madrid, SpainShow on map |
| Degree of Recognition | International |
Research Beacons, Institutes and Platforms
- Cancer
- Manchester Cancer Research Centre