Updated Analysis of Cohort G From the Phase 2 BELLWAVE-003 Study Evaluating Nemtabrutinib in Relapsed or Refractory Follicular Lymphoma

Introduction/Background/Significance: Nemtabrutinib, a potent, noncovalent, reversible Bruton tyrosine kinase inhibitor (BTKi) taken by mouth (PO) once daily (QD), has shown encouraging antitumor efficacy in multiple B-cell malignancies. The phase 2 BELLWAVE-003 study (NCT04728893) evaluated nemtabrutinib in participants with hematologic malignancies. Earlier results for cohort G of BELLWAVE-003 (median study follow-up, 6.1 months) showed that nemtabrutinib had a manageable safety profile and encouraging antitumor efficacy at the recommended phase 2 dose (RP2D) of 65 mg QD in participants with relapsed or refractory (R/R) follicular lymphoma (FL). Data from cohort G are reported 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, Richter transformation, mantle cell lymphoma, marginal zone lymphoma, FL, 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 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 51 participants with R/R FL received nemtabrutinib at the RP2D. The median study follow-up was 12.2 months (range, 0.7-23.2). The median age of participants was 59 years (range, 33-80); 28 (55%) were male, and 29 (57%) had Lugano stage IV disease. The median number of prior lines of therapy was 4 (range, 1-11). At data cutoff, the median time on therapy was 3.5 months (range, 0.2-15.6), with 11 participants (22%) remaining on treatment. The ORR was 43% (95% CI, 29-58). The median DOR was 3.3 months (95% CI, 2.8-not reached), and median PFS was 5.6 months (95% CI, 5.3-8.3). Median OS was not mature at the time of analysis. 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%), most frequently (≥5%) neutrophil count decreased (10%), thrombocytopenia (8%), neutropenia (6%), and platelet count decreased (6%). Dose reduction due to an AE were reported in 3 participants (6%; 1 with asthenia and blood creatinine increased, 1 with platelet count decreased, and 1 with sepsis). All-cause AEs leading to discontinuation occurred in 7 participants (14%; 1 each asthenia, congestive cardiac failure, COVID-19 pneumonia, traumatic subdural hemorrhage, thrombocytopenia, toxicity to various agents, and urticaria). Death due to all-cause AEs was reported in 3 participants (6%; 1 each respiratory tract infection, traumatic subdural hemorrhage, and medical aid in dying). No deaths were considered to be related to study treatment.

Conclusions: With extended follow-up, nemtabrutinib continued to show promising antitumor efficacy and manageable safety with no unexpected AEs in participants with heavily pretreated FL that had previously progressed on both chemoimmunotherapy and immunomodulatory therapy. The results warrant further evaluation of nemtabrutinib in participants with R/R FL.