CLL-638 Latest Results From an Ongoing Firstin-Human Phase 1a/B Study of NX-5948, a Selective Bruton's Tyrosine Kinase (BTK) Degrader, in Patients With Relapsed/Refractory CLL and Other B-Cell Malignancies

• Published in: Clinical lymphoma, myeloma and leukemia myeloma and leukemia, 2024-09, Vol.24, p.S360-S361
• Main Authors: Linton, Kim, Collins, Graham P., Forconi, Francesco, Shah, Nirav N., Dixit, Karan, Munir, Talha, Omer, Zulfa, El-Sharkawi, Dima, Doorduijn, Jeanette, Alencar, Alvaro, McKay, Pam, Riches, John, Gleeson, Mary, Lewis, David, Winter, Allison, Injac, Sarah, Shih, Ted, Nandakumar, Srinand, Tan, May, Cherala, Ganesh, Meredith, Erin, Danilov, Alexey
• Format: Article
• Language: English
• Subjects: B-cell malignancies; BTK degrader; BTK mutations; CLL; NX-5948; relapsed/refractory CLL
• ISSN: 2152-2650
• DOI: 10.1016/S2152-2650(24)01293-X

Emerging BTK inhibitor (BTKi)-resistance mutations and the scaffolding function of BTK present a need for approaches beyond BTKi for treating B-cell malignancies. NX-5948 is a novel, orally administered, small molecule that induces specific degradation of wild-type and mutant forms of BTK in B-cells by the cereblon E3 ligase complex. NX-5948 can cross the blood-brain barrier. NX-5948-301 is a Phase 1, first-in-human dose-escalation trial evaluating the safety, tolerability, and clinical activity of NX-5948 in patients with relapsed/refractory CLL and NHL/WM. Key eligibility criteria: ≥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. As of 17 April 2024, 79 patients (31 CLL, 48 NHL/WM) were enrolled at 6 daily oral dose levels: 50 mg (n=7), 100 mg (n=8), 200 mg (n=14), 300 mg (n=17), 450 mg (n=17), 600 mg (n=16). Median age: 67 (range 35–88) years; males: 65.8%; median prior lines of therapy: 4 (range 2–14), including for CLL: prior BTKi and BCL2i (87.1%). Baseline mutations in CLL were frequent: TP53, (46.7%), BTK (43.3%), PLCG2 (20.0%). NX-5948 was well tolerated across all doses with one treatment-related SAE and two discontinuations due to TEAEs. The most common TEAEs were purpura/contusion (35.4%, no Grade ≥3), thrombocytopenia (26.6%, 8.9% Grade ≥3), neutropenia (20.3%, 15.2% Grade ≥3). No new atrial fibrillation/flutter was reported. Rapid, robust, and sustained BTK degradation was observed in all patients regardless of absolute BTK starting level, tumor type or dose. Among 26 disease-evaluable patients with CLL, 18 clinical responses (PR/PR-L) were observed across all dose levels (ORR 69.2%). Findings demonstrate a tolerable safety profile of NX-5948 across B-cell malignancies. Deep clinical responses were observed in a heavily pre-treated population of patients with CLL, some with BTKi resistance mutations and high-risk molecular features. These data warrant continued investigation of NX-5948 in patients with CLL.