Nemtabrutinib in Relapsed Or Refractory Marginal Zone Lymphoma: Updated Efficacy and Safety From Cohort F of the Phase 2 BELLWAVE-003 Study
Introduction/Background/Significance: Nemtabrutinib, a potent, noncovalent, reversible Bruton tyrosine kinase inhibitor (BTKi) taken by mouth (PO) once daily (QD), has shown promising antitumor activity in various B-cell malignancies. The phase 2 BELLWAVE-003 study (NCT04728893) was designed to evaluate nemtabrutinib in participants with hematologic malignancies. In early results for cohort F of BELLWAVE-003 (median study follow-up, 9.2 months), nemtabrutinib at the recommended phase 2 dose (RP2D) of 65 mg QD showed antitumor activity and manageable safety in participants with marginal zone lymphoma (MZL) that is relapsed or refractory (R/R) to ≥2 prior lines of systemic therapies, including covalent BTKis. We present data from cohort F after additional follow-up.
Materials and Methods/Case Presentation/Objective: The multicenter, open-label, single-arm, phase 2 BELLWAVE-003 study enrolled participants with R/R chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, mantle cell lymphoma, MZL, Richter transformation, and Waldenström macroglobulinemia. Participants with R/R MZL must not have responded to prior chemoimmunotherapy and treatment with a covalent BTKi. Eligible participants received nemtabrutinib at the RP2D of 65 mg PO QD until disease progression, unacceptable toxicity, or withdrawal. The primary end point was ORR. Secondary end points included DOR per Lugano 2014 criteria by BICR and safety. Exploratory end points included PFS per Lugano 2014 criteria by BICR and OS. The data cut-off date was January 29, 2025.
Results/Description/Main Outcome Measures: A total of 23 participants with R/R MZL were treated with nemtabrutinib at the RP2D. The median follow-up for those receiving 65 mg was 10.3 months (range, 0.4-25.0). Participants were a median age of 68 years (range, 41 86); 13 (57%) were female, and 15 (65%) had Lugano stage IV disease. Participants received a median of 3 (range, 2-9) prior lines of therapy. The median duration of treatment was 4.7 months (range, 0.5-24.0), with 12 participants (55%) remaining on treatment at the data cut-off. The ORR was 52% (95% CI, 31-73) by BICR and 48% (95% CI, 27-69) by investigator review. At the time of analysis, the median DOR was 7.4 months (95% CI, 2.6-not reached), and the PFS and OS data were not mature. All-cause adverse events (AEs) of any grade occurred in 20 participants (87%). The most common all-cause AEs (≥25%) were pneumonia (30%), pyrexia (30%), anemia (26%), and diarrhea (26%). Grade 3 or 4 all-cause AEs were reported in 12 participants (52%). The most frequent all-cause grade 3 or 4 AEs (incidence ≥5%) were pneumonia (21%) and anemia (13%). Dose reduction due to an all-cause AE occurred in 3 participants (13%; 1 each due to fatigue, pneumonia, and weight decreased). Discontinuation due to an all-cause AE occurred in 3 participants (13%; 1 each due to anemia, febrile neutropenia, and pneumonia). No deaths due to an all-cause AE were reported.
Conclusions: With additional follow-up, nemtabrutinib continued to show promising antitumor activity in participants with heavily pretreated MZL who had progressed on both chemoimmunotherapy and covalent BTKi treatment. The safety profile remained manageable, with no unexpected AEs identified. These findings support the further investigation of nemtabrutinib in participants with R/R MZL.
