NX-2127-001, a First-in-Human Trial of NX-2127, a Bruton's Tyrosine Kinase-Targeted Protein Degrader, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia and B-Cell Malignancies

Introduction: Bruton's tyrosine kinase (BTK) is a key component of the B-cell receptor (BCR) signaling pathway. Targeting this pathway has proven highly effective in patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies. However, mutations in BTK develop with both covalent (cBTKi) and non-covalent inhibitors (ncBTKi) resulting in treatment resistance and disease progression. In addition, increased expression of the transcription factor IKZF3 may contribute to resistance to cBTKi/ncBTKi. Thus, novel therapeutic mechanisms are needed that target BCR signaling, particularly in patients whose disease has relapsed or is refractory (R/R) to existing BTK targeting therapies. NX-2127 is a novel small molecule that drives targeted BTK and IKZF3 degradation through ubiquitination and proteasomal degradation. This BTK degradation and immunomodulatory activity represents a novel mechanism of action and may overcome resistance to currently available novel agents including cBTKi and ncBTKi, addressing the unmet medical needs of patients whose disease is R/R to any BTKi (including ncBTKi) and a BCL2 inhibitor. Methods: NX-2127-001 is a first-in-human, multicenter, US-based, open-label, Phase 1 dose-escalation (Phase 1a) and cohort-expansion (Phase 1b) trial, evaluating the safety, tolerability, and preliminary efficacy of NX-2127 in adult patients with R/R CLL and B-cell malignancies. Patients receive NX-2127 orally once daily in 28-day cycles starting at 100 mg. We report the initial findings from the Phase 1a portion of the trial and the rationale for initiating the Phase 1b portion at 100 mg for patients with CLL. Results: As of 16 June 2022, 28 patients (17 CLL/SLL) were enrolled at dose levels 100, 200 and 300 mg. Patients were predominantly male (64.3%) with a median age of 76 (range 61-92) years. The most common adverse events in all patients are summarized in Table 1. One dose-limiting toxicity (DLT) of cognitive impairment was observed in a patient with CLL at 300 mg. No DLTs were observed in non-CLL indications. As of 16 June 2022, 17 patients with CLL were enrolled having received a median of 6 prior therapies (range 2-12). All have previously received a BTKi and 76.5% had also received venetoclax. Poor prognostic factors include unmutated IGHV (23.5%), mutations/deletions in TP53 (17.6%). Of the 14 CLL patient samples tested, mutations included BTK [C481 (29%), L528 (29%), T474 (14%), V416 (7%)] and BCL2 (14%). Mutations C481, V416 and L528 result in loss of BTK kinase function. A mean BTK degradation of 86% was observed in all patients by Cycle 1 Day 22 with a mean degradation of 83% in patients with CLL, resulting in decreased BCR signaling as measured by reduction of plasma CCL4. Immunomodulatory activity, as evidenced by Ikaros (IKZF1) degradation, was observed at all dose levels and in all indications. 10 patients with CLL continue on study (Figure 1). There were 12 response-evaluable patients with CLL. The best overall response rate (ORR) was 33% with evidence that ORR increases with longer follow up (ORR: 16.7% at 2 mos, 42.9% at 4 mos, 50% at 6 mos). Importantly, responses were noted in BTKi/BCL2 double-refractory patients and those who progressed on a ncBTKi. Conclusions: Double- and emerging triple-refractory CLL (patients who progressed on cBTKi, ncBTKi, and a BCL2 inhibitor) represents a major unmet medical need with no approved therapeutic options and poor survival. These patients may thus benefit from the interruption of BTK kinase-independent scaffolding signaling. In this first-in-human, first-in-class study of a BTK degrader, clinical responses and benefit were observed in heavily pretreated (median 6 prior therapies) patients with CLL who have poor prognostic factors, including those with BTK mutations resistant to cBTKi and ncBTKi, BCL2 mutations and those who were previously treated with both BTKi and BCL2 inhibitors. These data support further clinical development of NX-2127 in CLL, including expansion at the 100 mg dose level, and continued dose exploration for other B-cell malignancies. (NCT04830137). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal