Introduction: Covalent Bruton tyrosine kinase inhibitors (BTKis) are approved for use in patients with relapsed or refractory (R/R) marginal zone lymphoma (MZL). However, therapeutic alternatives remain limited for patients who experience disease progression or are unable to tolerate these therapies. Nemtabrutinib, a potent, noncovalent, reversible BTKi taken by mouth (PO) once daily (QD), has shown promising antitumor activity in various B-cell malignancies. Nemtabrutinib has additional activity versus ibrutinib against Src family kinases and kinases related to ERK signaling, which may produce robust responses. Analysis of nemtabrutinib-treated cell lines using next-generation sequencing showed a lack of mutation in BTK and PLCG2 domains, which contrasts with other covalent and noncovalent BTKis such as ibrutinib and pirtobrutinib, respectively. Furthermore, nemtabrutinib has also showed preclinical efficacy in cell lines carrying BTK mutations derived from patients treated with pirtobrutinib. The phase 2 BELLWAVE-003 study (NCT04728893) was designed to evaluate nemtabrutinib in participants with hematologic malignancies. After a median study follow-up of 9.2 months for cohort F of BELLWAVE-003, nemtabrutinib was shown to have antitumor activity and a manageable safety profile at the recommended phase 2 dose (RP2D) of 65 mg QD in participants with MZL that is R/R to ≥2 prior lines of systemic therapies, including covalent BTKis. Outcomes after additional follow-up are presented for cohort F.

Methods: 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 therapy with a covalent BTKi or prior chemoimmunotherapy. Eligible participants received nemtabrutinib at the RP2D of 65 mg PO QD until disease progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate (ORR). Secondary end points included duration of response (DOR) per Lugano 2014 criteria by blinded independent central review (BICR) and safety. Exploratory end points included progression-free survival (PFS) per Lugano 2014 criteria by BICR and overall survival (OS). The data cut-off date was January 29, 2025.

Results: Overall, 23 participants with R/R MZL were treated with nemtabrutinib at the RP2D. The median time from first dose to data cutoff was 10.3 months (range, 0.4-25.0) for participants who received 65 mg. The median participant age was 68 years (range, 41-86); 10 (43%) were male, and 15 (65%) had Lugano stage IV disease. Participants had received a median of 3 (range, 2-9) prior therapies. At data cutoff, the median treatment duration was 4.7 months (range, 0.5-24.0), with 12 participants (55%) remaining on treatment. The ORRs by BICR and investigator review were 52% (95% CI, 31-73) and 48% (95% CI, 27-69), respectively. The median DOR was 7.4 months (95% CI, 2.6-not reached). As of the data cutoff date, the median PFS and OS data were not mature. All-cause adverse events (AEs) of any grade were reported 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 occurred in 12 participants (52%); pneumonia (21%) and anemia (13%) were the most frequently observed AEs (incidence ≥5%). All-cause AEs resulting in dose reduction were observed 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 AE were reported.

Conclusion: With continued follow-up, nemtabrutinib showed sustained antitumor activity in heavily pretreated participants with MZL who had progressed after treatment with both chemoimmunotherapy and covalent BTKis. The safety profile remained consistent and manageable, with no new or unexpected AEs observed. These outcomes reinforce the rationale for further clinical exploration in R/R MZL.

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2025
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