Addition of BTK inhibitor orelabrutinib to rituximab improved anti-tumor effects in B cell lymphoma

Abstract

Bruton tyrosine kinase (BTK) inhibitor ibrutinib has been validated as an effective drug to treat B cell malignancies. Combined therapies comprising ibrutinib and anti-CD20 antibodies like rituximab were designed as a backbone in many clinical trials. However, the off-target inhibition of ibrutinib on interleukin-2 (IL-2)-inducible T cell kinase (ITK) may reduce rituximab’s antibody-dependent cellular cytotoxicity (ADCC) efficacy. Orelabrutinib (Orel), a novel BTK inhibitor, was designed with high selectivity to BTK. In our study, we demonstrated in preclinical models that orelabrutinib in combination with rituximab could preserve NK-cell-mediated ADCC induced by rituximab and enhanced the apoptosis of tumor cells in vitro . The addition of orelabrutinib to rituximab had produced promising combined anti-tumor effects in B cell lymphomas in vivo . Collectively, combination therapy of orelabrutinib with rituximab would benefit patients with B cell lymphoma, especially those with relapsed or refractory disease.

Orelabrutinib Combined With Lenalidomide and Immunochemotherapy for Relapsed/Refractory Primary Central Nervous System Lymphoma: A Retrospective Analysis of Case Series

“…As a preliminary study reported, the favorable blood-brain barrier permeability of orelabrutinib could induce a high CSF concentration of 20.10 ± 14.70 ng/mL ( 29 ), which may partly explain the better response in these patients. Besides, the synergistic effects of BTK inhibitor and Combination of drugs may be another reason for better response, such as the combination of orelabrutinib and rituximab ( 21 ), BTK inhibitor and lenalidomide ( 30 ). The combination therapy eliminates tumor cells from multiple aspects by killing tumor cells directly with chemotherapy, blocking proliferation pathways with targeted therapy, and modulating the tumor microenvironment with immunotherapy.…”

“…Besides, tirabrutinib as a BTK inhibitor was approved for the treatment of PCNSL ( 20 ). More importantly, per-clinical data showed the synergistic effect of orelabrutinib as a partner for combination therapy ( 21 ). Therefore, we conducted a retrospective analysis of 15 patients with r/r PCNSL to evaluate the efficacy and safety of combination therapy with rituximab, high-dose methotrexate (HD-MTX), and temozolomide (RMT), as well as orelabrutinib and lenalidomide.…”

SOHO State of the Art Updates and Next Questions: Targeted therapies and emerging novel treatment approaches for Waldenström Macroglobulinemia

“…Preclinical studies demonstrate orelabrutinib lacks inhibition of ITK (IL-2-inducible T-cell kinase), which preserves the function of NK cellmediated antibody-dependent cellular cytotoxicity (ADCC) as opposed to ibrutinib, in which ADCC is compromised. 37 Orelabrutinib is being investigated in a multicenter phase II trial in patients with R/R WM and early data were presented at ASH 2021. With 47 patients evaluable for analysis after 14 months of follow-up, the estimated 12-month PFS rate was 88%.…”

Bruton tyrosine kinase inhibitors in B-cell lymphoma: beyond the antitumour effect

“…However, a randomised single-centre study comparing ibrutinib plus rituximab with single-agent ibrutinib in patients with CLL showed that the combination therapy neither improved progression-free survival nor overall response rate (ORR) [ 47 ]. Preclinical data showed the combination of orelabrutinib and rituximab to enhance NK cell-induced ADCC and exert a synergistic antitumour effect in BCL [ 48 ]. Based on these findings, acalabrutinib plus obinutuzumab was considered to show high and durable responses in treatment-naïve patients and in those with R/R CLL [ 49 , 50 ].…”