Efficacy and Safety of the Bruton’s Tyrosine Kinase (BTK) Degrader NX-5948 in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): Updated Results from an Ongoing Phase 1a/b Study

Introduction: The increasing presence of BTK inhibitor (BTKi)-resistance mutations in CLL, along with BCR signaling through the kinase-independent scaffolding function of BTK, present a need for treatment modalities with an MoA that differs from BTKi. NX-5948 is a novel, orally administered, small molecule that induces specific degradation of wild-type and mutant forms of BTK by ubiquitination via the cereblon E3 ligase complex and subsequent proteasomal degradation. Here we report updated findings from a Phase 1a/b trial of NX-5948 in patients (pts) with R/R CLL.

Methods: NX-5948-301 is a Phase 1, first-in-human, dose-escalation trial evaluating the safety, tolerability, and clinical activity of NX-5948 in pts with R/R B-cell malignancies, including CLL and non-Hodgkin’s lymphoma (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 10 June 2024, 87 pts were enrolled across B-cell malignancies. In CLL (n=34), pts were treated at 6 daily oral dose levels: 50 mg (n=3), 100 mg (n=5), 200 mg (n=9), 300 mg (n=8), 450 mg (n=5), 600 mg (n=4). Median age was 68.0 (range 35–88) years, 64.7% were male, and the median number of prior lines of therapy was 4 (range 2–14). Prior therapies: BTKi (97.1%), pirtobrutinib (23.5%), BCL2i (91.2%), BTKi + BCL2i (88.2%), chemo/chemoimmunotherapy (79.4%), PI3Ki (32.4%), CAR-T (5.9%). In the 31 pts tested, baseline mutations were observed in TP53 (48.4%), BTK (41.9%, including C481S [n=7] and non-C481S [n=7]), PLCG2 (19.4%), and BCL2 (16.1%).

NX-5948 was well tolerated across all doses tested consistent with previously reported safety in the total study population including NHL. In CLL, median duration of safety follow-up was 4.7 (range 0.7–17.0) months. There was 1 treatment-emergent adverse event (TEAE) resulting in drug discontinuation (Gr 5 pulmonary embolism, not deemed treatment related), and no dose-limiting toxicities. Most common TEAEs were: purpura/contusion (44.1%, no Gr≥3); thrombocytopenia (23.5%, 2.9% Gr≥3); petechiae (29.4%, no Gr≥3); fatigue (20.6%, no Gr≥3); neutropenia (17.6%, 14.7% Gr≥3; pts with up to Gr 4 cytopenias were eligible for study participation); rash (23.5%, no Gr≥3, 2.9% SAE); headache (23.5%, no Gr≥3). There was no new onset atrial fibrillation/flutter or hypertension.

In 30 response-evaluable pts with CLL, the ORR was 76.7%. Best overall responses were: 20 PR; 3 PR-L, 5 SD and 2 PD. Responses were rapid, with the majority (18/23) seen at the first (8-week) scan; 22 responses were ongoing at data cut-off. In addition, 29/34 pts remain on treatment, with 5 beyond 12 cycles (1 cycle = 28 days) and 1 beyond 18 cycles. Treatment outcomes improved with longer time on treatment: 5 pts converted from SD to PR or PR-L, some as early as the second assessment.

Responses (PR, PR-L) were observed in pts with CNS involvement and other characteristics associated with difficult-to treat disease, including: prior BCL2i/BTKi (19 PR/PR-L and 5 SD/26), prior pirtobrutinib (4 PR/PR-L and 3 SD/7), TP53 mutations (9 PR/PR-L and 3 SD/13), and BTK mutations (8 PR/PR-L and 4 SD/12). Responders included pts with cBTKi resistance mutation C481S and ncBTKi resistance mutations L528W, T474I and V416L/M. Responses were also seen in pts with PLCG2 mutations (3 PR/PR-L and 2 SD/6).

Conclusions: These findings demonstrate that NX-5948 remains well tolerated in pts with CLL, with no clinically meaningful changes in safety profile observed with longer duration on study or at higher doses. Rapid and durable clinical responses that improved over time were observed in a population of pts with CLL who are heavily pretreated, including some with unfavorable genetic profiles associated with poor prognosis or BTKi resistance. Responses observed in pts with PLCG2 mutations support a mechanism whereby NX-5948 disrupts the BTK signaling complex, potentiating broader targeting of oncogenic pathways downstream of BTK. The Phase 1b dose-expansion portion of the study is underway; data from additional pts are expected for the presentation.