Background: Bruton tyrosine kinase inhibitors (BTKis) have transformed the treatment landscapes of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and certain B-cell neoplasms. However, the most common mechanism of resistance is due to mutations to BTK at the cysteine binding site (C481). Nemtabrutinib (MK-1026, formerly ARQ-531) is a noncovalent, potent inhibitor of both wild-type and ibrutinib-resistant C481S-mutated BTK. Initial results from the phase 1/2 BELLWAVE-001 study (NCT03162536) showed nemtabrutinib had a manageable safety profile and promising antitumor activity in heavily pretreated patients (pts) with relapsed or refractory (R/R) CLL/SLL, including pts whose disease progressed after prior covalent BTKis (Woyach et al. Blood. 2021;138:392). We present updated efficacy for all pts with CLL/SLL treated with nemtabrutinib 65 mg and safety for all pts with hematological malignancies who were treated with nemtabrutinib at the 65-mg dose. Methods: In this open-label, single-arm, phase 1/2 study, 9 expansion cohorts were initiated after determination of the preliminary nemtabrutinib recommended phase 2 dose (RP2D). Eligible pts with CLL/SLL were enrolled in cohort A (R/R CLL/SLL, with ≥2 prior therapies, including covalent BTKis, with documented C481 mutation), cohort B (R/R CLL/SLL with ≥2 prior therapies, intolerant to a BTKi, without C481 mutation), a dose-expansion group, or cohort I (food effect). Primary end points were ORR (per 2018 IWCLL criteria, by investigator), safety, and RP2D for pts with CLL/SLL. Secondary end points were DOR (including partial response [PR] with lymphocytosis), PFS, and safety. Efficacy analysis included CLL/SLL pts treated with nemtabrutinib 65-mg once-daily dose and safety included all pts with hematological malignancies who were treated with the nemtabrutinib 65-mg dose. Results: A total of 112 pts were enrolled and were treated with nemtabrutinib 65 mg once daily: 57 had CLL/SLL, 46 had B-cell non-Hodgkin lymphoma (NHL), 6 had Waldenstrom's macroglobulinemia, and 3 had a diagnosis of "other.” Among the 57 pts with CLL/SLL enrolled and treated with nemtabrutinib 65 mg (cohort A, n = 25; cohort B, n = 10; dose escalation, n = 13; cohort I, n = 9); median age was 66.0 years; 16 pts (28%) were female, and 50 (88%) had ECOG PS ≤1. Median (range) number of prior therapies was 4 (1-18); 54 pts (95%) had prior BTKi therapy; 24 (42%) had prior BTKi and BCL2i therapy. In addition, 36 pts (63%) had C481S-mutated BTK; 18 (32%) had TP53 mutation; 19 (33%) had del(17p); and 30 (53%) had unmutated IGHV. Of pts with CLL/SLL, 39 (68%) discontinued, most commonly because of clinical disease progression [PD] and "other” causes (10 [18%] each); 8 (14%) discontinued owing to adverse events (AEs). Among the 24 pts with CLL/SLL who received prior BTKis and BCL-2is, 19 (33%) discontinued, most commonly because of clinical PD and other causes (6 [11%] each) and AEs (4 [7%]). At data cutoff (April 08, 2022), median (range) follow-up for pts with CLL/SLL was 8.1 months (0.1-38.8); 32 pts had objective response (ORR, 56% [95% CI, 42-69]; complete response, 2; PR, 15; PR with residual lymphocytosis, 15). Among the 32 pts who responded, median DOR was 24.4 months (95% CI, 13.9-not evaluable [NE]); median PFS was 26.3 months (95% CI, 10.1-NE). Efficacy by key subgroups is presented in the table. Among all pts with B-cell malignancies treated with nemtabrutinib at the 65-mg dose (N = 112) included in the safety analysis, 82 (73%) had any-grade treatment-related AEs (TRAEs), most common (≥10%) were dysgeusia (21%); decreased neutrophils (20%); fatigue (13%); nausea and decreased platelets (12%, each); and diarrhea and hypertension (10%, each). Grade 3 or 4 TRAEs occurred in 45 pts (40%); most common (≥5%) were decreased neutrophils (17%) and decreased platelets and lymphocytosis (5%, each). Treatment-related discontinuations occurred in 15 pts (13%). No deaths were attributed to treatment. Conclusion: Nemtabrutinib 65 mg continued to show promising and durable antitumor activity with a manageable safety profile in a highly relapsed/refractory population who had prior therapy with novel agents. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal