Non-Covalent BTK Inhibitors—The New BTKids on the Block for B-Cell Malignancies

Abstract

The B-cell receptor signalling pathway plays a critical role in development of B-cell malignancies, and the central role of Bruton’s tyrosine kinase (BTK) activation in this pathway provides compelling rationale for BTK inhibition as a therapeutic strategy for these conditions. Covalent BTK inhibitors (BTKi) have transformed the treatment landscape of B-cell malignancies, but adverse events and treatment resistance have emerged as therapeutic challenges, with the majority of patients eventually discontinuing treatment due to toxicity or disease progression. Non-covalent BTKi have alternative mechanisms of binding to BTK than covalent BTKi, and therefore offer a therapeutic alternative for patients with B-cell malignancies, including those who have been intolerant to, or experienced disease progression during treatment with a covalent BTKi. Here, we summarise the clinical data, adverse events and mechanisms of resistance observed with covalent BTKi and describe the emerging data for non-covalent BTKi as a novel treatment for B-cell malignancies.

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

“…Reversible BTKi, such as pirtobrutinib and vecabrutinib, bind BTK non-covalently and do not require C481 to be present [84], thus overcoming this resistance mechanism. They can therefore inhibit BTK in the presence of the C481S mutation, and non-selective reversible BTK-i, including MK1026, may also overcome mutations within PLCG2 [85]. Results from ongoing studies of alternative BTK inhibitors will help define their role in CLL therapy as single drugs or in combination.…”

Targeted Agents in the Treatment of Indolent B-Cell Non-Hodgkin Lymphomas

“…The development of highly potent, selective, non-covalent, reversible inhibitors have proven effective in patients with disease progressing on covalent BTK inhibitors and those harbouring a BTK C481 mutation [ 40 , 41 ]. At least four such agents have progressed through various phases of development, with pirtobrutinib (LOXO-305), vecabrutinib (SNS-062) and nemtabrutinib (MK-1026; formerly ARQ-531) the most advanced [ 39 , 42 , 43 ]. The phase 1/2 BRUIN study tested pirtobrutinib monotherapy in 323 patients with relapsed or refractory B-NHL, the majority of whom had prior exposure to a BTK inhibitor, with an overall response of 68% in WM ( n = 26), 50% in FL (n = 12) and 22% in MZL (n = 9) observed.…”

Targeted Therapy in Leukaemia, Lymphoma and Myeloma

“…This Special Issue of the Journal of Personalized Medicine entitled "Targeted therapy in Leukaemia, Lymphoma and Myeloma" contains 10 publications authored by experts working in a diverse range of haematological cancers including B cell non-Hodgkin lymphoma [22][23][24][25], T-cell non-Hodgkin lymphoma [26], Multiple Myeloma [27][28][29], Chronic Lymphocytic Leukaemia [23,25,28], Acute Myeloid Leukaemia [28,30] and Acute Lymphoblastic Leukemia [31].…”

“…These neoplasms are biologically distinct but share biological features which enable certain agents to be used across a broad range of tumours including BCL2 inhibitors in B cell non-Hodgkin lymphoma, Multiple Myeloma, Chronic Lymphocytic Leukaemia, Acute Myeloid Leukaemia [28,30]; hypomethylating agents in T cell Lymphoma and Acute Myeloid Leukaemia [26,30]; BTK inhibitors in Chronic Lymphocytic Leukaemia and B cell lymphoma [25]; Cereblon-Interacting Small Molecules in Follicular Lymphoma and Myeloma [22,27,29]; and Bispecific antibodies in B cell lymphoma and B Lymphoblastic leukaemia [24,31].…”