Genomic assessment of acquired mutations in participants with CLL/SLL treated with nemtabrutinib in the Phase 2 bellwave-003 study Free

Introduction: Nemtabrutinib is a once daily, noncovalent, reversible Bruton tyrosine kinase inhibitor (BTKi) that targets BTK and other kinases involved in B-cell receptor signaling. Analysis of nemtabrutinib-treated cell lines using next-generation sequencing showed a lack of mutation in BTK and PLCγ2, in contrast with other covalent and noncovalent BTKi such as ibrutinib and pirtobrutinib, respectively (Qi et al, Blood Adv, 2023). Nemtabrutinib has also demonstrated preclinical activity across a panel of BTK mutant cells lines carrying both C481 and non-C481 mutations derived from participants (pts) treated with pirtobrutinib, like T474I and L528W (Wang et al, NEJM, 2022). Moreover, nemtabrutinib has also shown activity in preclinical models with high-risk mutations such as TP53 (Sartori et al, Mol Ther, 2023), supporting its potential as a therapeutic option in BTKi-resistant and genetically high-risk B cell malignancies. In this exploratory analysis we present data on mutations in genes such as BTK, PLCγ2 (acquired resistance mutations), and TP53, MAPK, NOTCH, MYD88, SF3B1, ATM, BCL2 (prognostic mutations), and efficacy outcomes in pts with CLL/SLL treated with nemtabrutinib in the phase 2 BELLWAVE-003 study.

Methods:The phase 2 BELLWAVE-003 study enrolled pts with R/R CLL/SLL to receive nemtabrutinib at the RP2D of 65 mg once daily until unacceptable toxicity, disease progression (PD), or withdrawal. Eligible pts with R/R CLL/SLL must have prior covalent BTKi and BCL2i and be considered relapsed/refractory to both classes of treatment, at least one prior line of therapy and BTKi treatment-naïve, or with 17p deletion or TP53 mutation. Sequencing was performed at various timepoints through end of treatment (EOT) utilizing a comprehensive genomic profiling assay tailored for hematologic malignancies. Next-generation sequencing on DNA from >400 cancer-related genes was included. Data cutoff was Jan 29, 2025.

Results: A total of 92 pts with CLL/SLL were biomarker evaluable (having both baseline and EOT or proxy samples [≥ cycle 7]). Among biomarker evaluable pts, 8 (9%) did not have a mutation of interest at baseline. In contrast, a majority of pts entering the study, 84 (88%), had one or more resistance or poor prognosis mutations at baseline, including 28 (30%) with BTK C481S or other C481 substitutions, 7(8%) with acquired gain-of-function mutations in PLCγ2, 3 (3%) with BTK mutations other than at C481, and 78 (85%) with a poor prognostic mutation in evaluated genes of interest (TP53, MAPK, NOTCH1, SF3B1, ATM or BCL2). Following treatment with nemtabrutinib, 17 (18%) acquired a mutation in genes associated with poor prognosis including TP53 (3 [3%]), MAPK (1 [1%]), NOTCH1 (5 [5%]), SF3B1 (5 [5%]), ATM (4 [4%]), and BLC2 (1 [1%]). Two (2%) pts acquired a resistance mutation in PLCγ2, making the mutation rare, and no pts acquired a BTK C481 or non-C481 resistance mutation. Both pts who acquired a PLCγ2 mutation had extensive prior treatment (e.g. >4 lines); efficacy outcomes were pending central review at the time of data cut-off. A total of 32 (35%) pts were ongoing with study treatment at data cut-off. Among biomarker evaluable pts, 63 (68%) were evaluable for best overall response by central review. A best response of partial response or partial response with lymphocytosis, as per 2018 iwCLL guidelines, was observed in 42 (67%) pts, 13 had SD, 4 had PD, and 4 were non-evaluable. Of 42 pts that responded, 34 (81%) had poor prognostic mutations at baseline and 11 (26%) had BTK or PLCγ2 mutations at baseline. None acquired a canonical BTK resistance mutation including a PLCγ2, BTK C481, or BTK non-C481 variant at EOT or EOT proxy. A total of 23 (37%) had PD at last assessment.

Conclusion:These data show that across all biomarker-evaluable pts with R/R CLL/SLL receiving nemtabrutinib in BELLWAVE-003, acquired resistance mutations to BTKi were rare, regardless of response. While BTK mutations are the most frequent mechanism of resistance to covalent BTKi and have also been reported after treatment with non-covalent BTKi, none were detected in pts treated with nemtabrutinib. These data support the rationale for systematically evaluating the molecular basis of acquired resistance, which may differ from mechanisms observed with other noncovalent BTKi. Future analyses with more mature data aim to assess clonal evolution at later timepoints and identify potential late-emerging or atypical resistance mutations.