Nemtabrutinib in participants with relapsed or refractory follicular lymphoma: Updated efficacy and safety from cohort g of the phase 2 bellwave-003 study

Abstract Introduction: Covalent Bruton tyrosine kinase inhibitors (BTKis) have shown clinical activity as monotherapy in relapsed or refractory (R/R) follicular lymphoma (FL); however, outcomes such as response rates and progression-free survival (PFS) have generally been limited. 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 assess nemtabrutinib in participants with various hematologic malignancies. Initial results for cohort G of BELLWAVE-003 (median study follow-up, 6.1 months) showed that nemtabrutinib had a manageable safety profile and promising antitumor efficacy at the recommended phase 2 dose (RP2D) of 65 mg QD in participants with R/R FL. We present results from cohort G of BELLWAVE-003 after additional follow-up. Methods The multicenter, open-label, single-arm phase 2 BELLWAVE-003 study enrolled participants with R/R CLL/SLL, FL, mantle cell lymphoma, marginal zone lymphoma, Richter transformation, and Waldenström macroglobulinemia. Participants with FL whose disease was R/R to chemoimmunotherapy and immunomodulatory agents received nemtabrutinib at the RP2D of 65 mg PO QD until unacceptable toxicity, disease progression, or withdrawal. The primary end point was objective response rate (ORR). Secondary end points included duration of response (DOR) per Lugano 2014 criteria by BICR and safety. Exploratory end points included PFS per Lugano 2014 criteria by BICR and overall survival (OS). The data cutoff date was January 29, 2025. Results: A total of 51 participants with R/R FL were treated with nemtabrutinib at the RP2D. The median study follow-up, defined as time from first dose to the data cutoff date, was 12.2 months (range, 0.7-23.2). The median age of participants was 59 years (range, 33-80); 23 participants (45%) were female, and 29 (57%) had Lugano stage IV disease. Participants had received a median of 4 (range, 1-11) prior lines of therapy. The median duration of treatment was 3.5 months (range, 0.2-15.6), with 11 participants (22%) remaining on treatment at the data cutoff date. The ORR was 43% (95% CI, 29-58); 3 participants (6%) had a complete response, and 19 (37%) had a partial response. At the time of analysis, the median DOR was 3.3 months (95% CI, 2.8-not reached), median PFS was 5.6 months (95% CI, 5.3-8.3), and median OS was not mature. All-cause adverse events (AEs) of any grade were reported in 49 participants (96%). The most common all-cause AEs (≥20%) were neutrophil count decreased (24%) and platelet count decreased (20%). Grade 3 or 4 all-cause AEs occurred in 21 participants (41%). The most common grade 3 or 4 all-cause AEs (≥5%) were neutrophil count decreased (10%), thrombocytopenia (8%), neutropenia (6%), and platelet count decreased (6%). Dose reduction due to an all-cause AE were reported in 3 participants (6%; 1 with asthenia and blood creatinine increased, 1 with platelet count decreased, and 1 with sepsis). Discontinuation due to an all-cause AE occurred in 7 participants (14%; 1 each with asthenia, congestive cardiac failure, COVID-19 pneumonia, traumatic subdural hemorrhage, thrombocytopenia, toxicity to various agents, and urticaria). Death due to an all-cause AE occurred in 3 participants (6%; 1 each from respiratory tract infection, traumatic subdural hemorrhage, and medical aid in dying). No treatment-related AE resulting in death was reported. Conclusion With additional follow-up, nemtabrutinib continued to show promising antitumor efficacy in participants with FL who had received multiple prior lines of therapy and had progressed on both chemoimmunotherapy and immunomodulatory therapy. The safety profile remained manageable, with no unexpected AEs observed. These results support the ongoing clinical evaluation of nemtabrutinib in the R/R setting for FL.