Introduction: Although BTK inhibitors (BTKi) are effective therapeutics in the treatment of B cell malignancies, emerging BTK resistance mutations in chronic lymphocytic leukemia (CLL), as well as potential growth-promoting kinase-independent scaffolding function of BTK, present a need for improved or new approaches. Additionally, preclinical and clinical data in non-Hodgkin's lymphoma (NHL) suggest that drugs modulating cereblon may synergize with BTKi to provide a therapeutic effect. NX-2127 is an oral, first-in-class, dual-function small molecule degrader that combines BTK degradation with the immunomodulatory activity of an Ikaros and Aiolos degrader. Preliminary safety of NX-2127 in patients across B cell malignancies and efficacy in patients with CLL have been presented previously [Mato et al. 2022; Danilov et al. 2023]. Here we report further safety and efficacy follow-up in patients with CLL and efficacy data in patients with NHL enrolled to date. Methods: NX-2127-001 (NCT04830137) is a first-in-human, multicenter, open-label, dose-escalation (Phase 1a) and cohort-expansion (Phase 1b) trial evaluating the safety and preliminary efficacy of NX-2127 in adults with relapsed/refractory B cell malignancies, including CLL, diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and Waldenstrom's macroglobulinemia (WM). NX-2127 is administered orally once daily in 28-day cycles. Results: As of 9 June 2023, 47 patients were enrolled and treated with NX-2127 at once-daily doses of 100 mg (n=28), 200 mg (n=10), and 300 mg (n=9). Patients were predominantly male (66%), with a median age of 74 (range 50-92) years. Twenty-nine patients were treated for CLL/small lymphocytic lymphoma, 5 DLBCL (2 GCB [Germinal-center B-cell-like], 3 non-GCB), 5 MCL, 3 MZL, 3 WM, and 2 FL. Patients enrolled were heavily pretreated with median prior lines of therapy of 4 (range 2-10) in NHL and 5 (range 2-11) in CLL. Prior treatments in patients with CLL comprised: BTKi 100% (including covalent [cBTKi] and non-covalent [ncBTKi] inhibitors); BCL2 inhibitor 76%, with a large proportion of CLL patients exhibiting BTKi resistance mutations at baseline. Prior treatments in patients with NHL included: BTKi 72% (cBTKi and ncBTKi); bispecific antibody 1/18; bispecific antibody and CAR-T 1/18. There were two reported dose-limiting toxicities: one previously reported cognitive disturbance in a patient with CLL treated at 300 mg; and neutropenia in a patient with MZL treated at 300 mg. The most common any grade treatment-emergent adverse events (TEAEs) were fatigue (48.9%), neutropenia (42.6%) and hypertension (36.2%, see Table). The most common grade ≥3 TEAEs were neutropenia (38.3%), hypertension (14.9%) and anemia (12.8%). Contusion was reported in 27.7% of patients (all below grade 3), atrial fibrillation in 12.8% of patients (6.4% grade ≥3). Most common reasons for treatment discontinuation were progressive disease (PD, 25.5%) and AE (21.3%). Median follow-up for the study was 9.5 (range 0.1-24.3) months. NX-2127 exhibited dose-dependent pharmacokinetics (PK) with a mean half-life of 2-4 days across cohorts. Rapid, robust and sustained BTK degradation was observed in all patients, regardless of their absolute BTK starting level, tumor type, or dose level of NX-2127 (Figure). In addition, degradation of the cereblon neo-substrate Ikaros was observed. Among the efficacy evaluable patients with CLL, there were 9 PRs/PR with rebound lymphocytosis; additionally, 11 patients had SD at the time of data cut-off and 4 had PD. Two patients with WM were treated and efficacy evaluable (1 SD, 1 PD). Among the efficacy evaluable patients with NHL, there were 2 CRs and 1 PR; additionally, 3 patients had SD, and 5 had PD. Two CRs are ongoing with 9.2 and 11.8 months of duration. Conclusion: This first-in-human study of NX-2127 is actively enrolling and dose-expansion cohorts in DLBCL and MCL have been initiated at the 300 mg daily dose. Findings include dose-dependent PK accompanied by degradation of BTK and Ikaros. Encouraging and persistent responses were observed in heavily pretreated patients with relapsed/refractory CLL and NHL with a manageable safety profile. These data support the treatment concept of combining immunomodulatory activity and BTK degradation in a single molecule and support further development of NX-2127 in B cell malignancies.