Reference Detail

Ref Type

Journal Article

PMID

(34662393)

Authors

Jebaraj BMC, Müller A, Dheenadayalan RP, Endres S, Roessner PM, Seyfried F, Walliser C, Wist M, Qi J, Tausch E, Mertens D, Fox JA, Debatin KM, Meyer LH, Taverna P, Seiffert M, Gierschik P, Stilgenbauer S

Title

Evaluation of vecabrutinib as a model for noncovalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood	139	6	2022 02 10	859-875	Blood

URL

Abstract Text

Covalent Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop as the result of a mutation in cysteine 481 of BTK (C481S), which prevents irreversible binding of the drugs. In the present study we performed preclinical characterization of vecabrutinib, a next-generation noncovalent BTK inhibitor that has ITK-inhibitory properties similar to those of ibrutinib. Unlike ibrutinib and other covalent BTK inhibitors, vecabrutinib showed retention of the inhibitory effect on C481S BTK mutants in vitro, similar to that of wild-type BTK. In the murine Eμ-TCL1 adoptive transfer model, vecabrutinib reduced tumor burden and significantly improved survival. Vecabrutinib treatment led to a decrease in CD8+ effector and memory T-cell populations, whereas the naive populations were increased. Of importance, vecabrutinib treatment significantly reduced the frequency of regulatory CD4+ T cells in vivo. Unlike ibrutinib, vecabrutinib treatment showed minimal adverse impact on the activation and proliferation of isolated T cells. Lastly, combination treatment with vecabrutinib and venetoclax augmented treatment efficacy, significantly improved survival, and led to favorable reprogramming of the microenvironment in the murine Eμ-TCL1 model. Thus, noncovalent BTK/ITK inhibitors, such as vecabrutinib, may be efficacious in C481S BTK mutant CLL while preserving the T-cell immunomodulatory function of ibrutinib.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BTK C481S	chronic lymphocytic leukemia	sensitive	Vecabrutinib	Preclinical - Cell culture	Actionable	In a preclinical study, Vecabrutinib (SNS-062) inhibited viability of a chronic lymphocytic leukemia cell line harboring BTK C481S (PMID: 34662393).	34662393
BTK E41K	Advanced Solid Tumor	predicted - sensitive	Vecabrutinib	Preclinical - Biochemical	Actionable	In a preclinical study, Vecabrutinib (SNS-062) inhibited Plcg2 activity in cells expressing BTK E41K in an in vitro assay (PMID: 34662393).	34662393
BTK E41K BTK C481S	Advanced Solid Tumor	predicted - sensitive	Vecabrutinib	Preclinical - Biochemical	Actionable	In a preclinical study, Vecabrutinib (SNS-062) inhibited Plcg2 activity in cells expressing BTK E41K and BTK C481S in an in vitro assay (PMID: 34662393).	34662393