Nemtabrutinib, a Noncovalent Reversible BTK Inhibitor in Relapsed or Refractory Marginal Zone Lymphoma: Results from the Phase 2 Bellwave-003 Study
Authors: Zinzani Pier Luigi , Dupont Juan Carlos , Tucci Alessandra , Yang Jing , Xu Yan , Leng Siyang , Ozcan Muhit 
Published: December 2024

Introduction: Covalent Bruton tyrosine kinase inhibitors (BTKi) are approved for the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL), but patients who progress or are intolerant may have limited subsequent options. Nemtabrutinib is a once daily, potent, noncovalent, reversible BTKi with a distinct kinase profile that inhibits BTK and other B-cell receptor relevant kinases. Here, we present safety and efficacy results from the phase 2 BELLWAVE-003 study (NCT04728893) of nemtabrutinib at the recommended phase 2 dose (RP2D) in participants (pts) with R/R MZL.
Methods: The multicenter, open-label, single-arm phase 2 BELLWAVE-003 study enrolled pts with R/R CLL/SLL, Richter transformation, mantle cell lymphoma, MZL, follicular lymphoma, and Waldenstrom's macroglobulinemia. Pts with R/R MZL must have had prior chemoimmunotherapy and a covalent BTKi. Eligible pts received nemtabrutinib at the RP2D of 65 mg once daily until unacceptable toxicity, disease progression, or withdrawal. The primary endpoint was objective response rate by investigator assessment per Lugano 2014 criteria. Additional endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety and tolerability. The data cut-off was April 19, 2024.
Results: At data cut-off, 12 pts with R/R MZL treated at RP2D were enrolled. The median (range) follow-up was 9.2 mo (1.0-14.7) in all treated pts. These pts had a median age of 73 years (range, 53-86) and 7 (58%) were male. Seven (58%) had extranodal disease, 3 (25%) nodal, and 2 (17%) splenic. Nine (75%) pts had Lugano stage IV disease, and 8 (75%) had baseline hemoglobin &lt;12 g/dL. The median (range) number of prior lines of therapy was 4 (3-9); all pts received prior chemoimmunotherapy and covalent BTKi, and 5 (42%) pts were refractory to last therapy.
The median (range) time on therapy was 7.1 mo (1.0-14.7), with 8 (67%) pts still on therapy at data cut-off. Among 11 efficacy evaluable pts, the ORR was 64% (95% CI, 31-89), with 3 (27%) CR and 4 (36%) PR; 3 (27%) pts had stable disease. The median (range) DOR was not reached (NR) (8.5-NR) with median (range) time to response of 2.9 mo (2.6-5.5). Median PFS in the as treated population was 11.0 mo (95% CI, 2.7-NR). Median OS was NR (95% CI, NR), with 12-mo OS rate of 100%.
Any grade adverse events (AEs) occurred in all pts, most commonly diarrhea in 4 (33%) pts, pneumonia (4 [33%]), anemia (3 [25%]), and fatigue (3 [25%]). Grade 3-4 AEs occurred in 7 (58%) pts, with grade 3-4 anemia in 2 (17%) pts, and neutropenia in 1 (8%) pt. No atrial fibrillation or other arrhythmia was observed. Dose reduction due to an AE occurred in 2 (17%) pts (fatigue, pneumonia), and discontinuation due to an AE occurred in 2 (17%) pts (anemia, pneumonia). There were no deaths due to an AE.
Conclusion: Nemtabrutinib demonstrated promising antitumor activity in a heavily refractory population of pts with marginal zone lymphoma post chemoimmunotherapy and covalent BTKi therapy. Safety was manageable, and no new safety signals were identified. Enrollment and follow-up are ongoing.