Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions

Abstract

Zanubrutinib (BGB-3111, Brukinsa®, BeiGene) is a next-generation irreversible inhibitor of Bruton’s tyrosine kinase (BTK), developed by BeiGene in 2012 for the treatment of B-cell malignancies. It was designed to minimize off-target inhibition of TEC- and EGFR-family kinases. Zanubrutinib is more selective than ibrutinib for BTK versus EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, BLK and TEC. In addition, compared to ibrutinib, zanubrutinib has improved oral absorption and better target occupancy. Zanubrutinib demonstrated a lower incidence of off-target toxicities and reduced severity than ibrutinib. Moreover, zanubrutinib is similar to acalabrutinib, with less activity against TEC and ITK. The preliminary phase 1 results suggest that zanubrutinib has clinical activity and the drug is well tolerated in patients with B-cell lymphoid malignancies. Recent clinical trials have found it to demonstrate excellent efficacy and good tolerability in patients with chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia (WM) and mantle cell lymphoma (MCL). In recent phase 3 studies, zanubrutinib was compared with ibrutinib in patients with relapsed/refractory (R/R) MW and RR CLL. In both trials, zanubrutinib was found to demonstrate clinically meaningful advantages in safety and tolerability over ibrutinib; in particular, it was associated with a lower risk of atrial fibrillation/flutter and major bleeding events. In the recent SEQUOIA study, comparing zanubrutinib with bendamustine and rituximab (BR) in patients with previously untreated CLL, zanubrutinib significantly improved progression-free survival versus BR, with an acceptable safety profile consistent with previous studies. Zanubrutinib also demonstrated good activity and tolerability in patients with R/R MCL, marginal zone lymphoma and follicular lymphoma. Trials examining the efficacy and safety of the combination of zanubrutinib with obinutuzumab venetoclax and other drugs are ongoing. This review summarizes the clinical efficacy and safety of zanubrutinib in lymphoid malignancies.

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

“…This results in the reduced off-target inhibition of other kinases in the TEC family, including EGFR and ITK, leading to fewer adverse events [ 54 , 55 ]. Compared to ibrutinib-based therapy, treatment with second-generation BTKi is burdened by a lower incidence of cardiovascular adverse events, such as atrial fibrillation/flutter and bleeding [ 54 , 55 , 56 ]. In particular, a recent meta-analysis that compared standard treatment versus second-generation BTKi therapy in B cell malignancies reported no difference in death rate due to cardiovascular adverse events [ 57 ].…”

Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL)

“…Like ibrutinib and acalabrutinib, it binds to the C481 residue of BTK. However, its design allows more specific binding with fewer off-target effects potentially lowering the number of AEs (Figure 2) [30,47]. In a recent update from the SEQUOIA study, results show that there were fewer AE's and less discontinuation of treatment, with an impressive 82% progression-free survival (PFS) rate at 42 months [48].…”

“…In a recent update from the SEQUOIA study, results show that there were fewer AE's and less discontinuation of treatment, with an impressive 82% progression-free survival (PFS) rate at 42 months [48]. Likely due to its structure, there are fewer cases of atrial fibrillation [30] making it safer for patients on clotting medications [49].…”

“…Considering the significant involvement of BTK and the impact it has on B-cells when dispossessed, scientists investigated the efficacy of inhibiting BTK in B-cell malignancies. As a cell signal blocker, these treatments attach to the ATP binding site of BTK, effectively preventing BTK from activating the BCR pathway [12,29,30]. Unable to proliferate, malignant b-cells stop growing and spreading, allowing for tumor reduction [19].…”