Non-Covalent Bruton’s Tyrosine Kinase Inhibitors in the Treatment of Chronic Lymphocytic Leukemia

SIMPLE SUMMARY: Non-covalent Bruton’s tyrosine kinase inhibitors (ncBTKi) are being investigated for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL). These agents hold promise for the treatment of CLL, especially CLL requiring treatment after prior discontinuation of covalent Bruton’s tyrosine kinase inhibitors such as ibrutinib, acalabrutinib and zanubrutinib for either intolerance or progression of disease. This review outlines current preclinical and clinical data for the use of ncBTKi in CLL. Recently reported data has shown durable responses for the ncBTKi pirtobrutinib in CLL patients previously treated with a covalent BTKi with a median PFS of 19.6 months. We also discuss recently discovered mechanisms of resistance to ncBTKis, including acquired mutations in the BTK protein not in the C481 position. In addition, we highlight ongoing clinical trials that are incorporating ncBTKis in CLL as monotherapy or in combination therapies with other agents. The results of these trials as well as ongoing research regarding mechanisms of resistance to ncBTKi and covalent Bruton’s Tyrosine Kinase inhibitors will be important to determine where ncBTKi may fit into the treatment of CLL. ABSTRACT: Covalent Bruton’s tyrosine kinase inhibitors (cBTKi) have led to a paradigm shift in the treatment of chronic lymphocytic leukemia (CLL). These targeted oral therapies are administered as standard treatments in both the front-line and relapsed and/or refractory settings. Given their administration as a continuous therapy with a “treat-to-progression” strategy, limitations of their use include discontinuation due to toxicity or from progression of the disease. Non-covalent Bruton’s tyrosine kinase inhibitors (ncBTKi) distinguish themselves by binding reversibly to the BTK target, which may address the limitations of toxicity and acquired resistance seen with cBTKi. Several ncBTKis have been studied preclinically and in clinical trials, including pirtobrutinib and nemtabrutinib. Pirtobrutinib, which is now FDA approved for relapsed and/or refractory mantle cell lymphoma (MCL), has shown outstanding safety and preliminary efficacy in CLL in phase 1 and 2 clinical trials, with phase 3 trials underway. This agent may fill an unmet medical need for CLL patients requiring treatment after a cBTKi. Pirtobrutinib is particularly promising for the treatment of “double exposed” CLL, defined as CLL requiring treatment after both a cBTKi and venetoclax. Some patients have now developedacquired resistance to pirtobrutinib, and resistance mechanisms (including novel acquired mutations in BTK outside of the C481 position) have been recently described. Further study regarding the mechanisms of resistance to pirtobrutinib in patients without prior cBTKi exposure, as well as the potential for cross-resistance between cBTKi and ncBTKis, may be important to help inform where ncBTKis will ultimately fit in the treatment sequencing paradigm for CLL. An emerging clinical challenge is the treatment of CLL after ncBTKi discontinuation. Novel therapeutic strategies are being investigated to address the treatment of patients following disease progression on ncBTKis. Such strategies include novel agents (BTK degraders, bispecific antibody therapy, CAR T-cell therapy, PKC-beta inhibitors) as well as combination approaches incorporating a ncBTKi (e.g., pirtobrutinib and venetoclax) that may help overcome this acquired resistance.