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

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.

B cell receptor signaling and associated pathways in the pathogenesis of chronic lymphocytic leukemia

“…Noncovalent (reversible) BTK inhibitors differ from the previously mentioned compounds in noncovalently binding BTK, resulting in selective inhibitory effects regardless of a C481S BTK mutation ( 148 ). Noncovalent BTK-inhibitory drugs were generated in order to successfully improve the treatment in R/R CLL patients with BTK-inhibitor resistance bearing a BTK C481S mutation.…”

Molecular Insights into the Impact of Mutations on the Binding Affinity of Targeted Covalent Inhibitors of BTK

“…As is typical with kinase small-molecule drug discovery, the emergence of resistance mutations (e.g., C481S and T474M in BTK) is a critical concern for clinical efficacy and treatment. , These mutations impact the binding affinity and overall target engagement of inhibitors against BTK, especially mutation in the C481 position in the context of covalent inhibitors. Recent noncovalent BTK inhibitors such as pirtobrutinib and nemtabrutinib, including novel therapeutic protein degraders, hold promise for addressing some of the limitations of acquired resistance in relapsed and/or refractory patients previously treated with covalent BTK inhibitors. − Nevertheless, accurately predicting the effect of mutations in drug binding and pathogenesis could inform targeted approaches in drug discovery, as well as shed light on drug resistance mechanisms. With the advent of increased computer power, hardware technology, and algorithmic development, advanced computational approaches such as molecular dynamics and binding free energy calculations, are becoming routine in early stage drug discovery applications.…”

Targeting BTK in B Cell Malignancies: From Mode of Action to Resistance Mechanisms

“…Although chemoimmunotherapy (CIT) has represented the standard of care in B cell malignancies, in recent years, targeting Bruton tyrosine kinase (BTK) with innovative drugs, namely BTK inhibitors (BTKi), has revolutionized the therapeutic landscape for these diseases [ 3 ]. Currently, BTKi can be distinguished into covalent and non-covalent BTKi, according to the precise mode of action [ 4 , 5 ].…”