Orelabrutinib plus tafasitamab and lenalidomide showed “synergistic effects” in preclinical models of B-cell malignancies and are now under evaluation in a phase I trial, according to a recent study.
The results of the study were presented during the 2023 American Association for Cancer Research Annual Meeting in Orlando, Florida.
Researchers conducted the study to investigate combining orelabrutinib with tafasitamab and lenalidomide in preclinical B-cell tumor models.
They measured the antibody-dependent cellular cytotoxicity activity of tafasitamab alone, in combination with lenalidomide and orelabrutinib, and in combination with ibrutinib. The study’s authors tested the agents in co-cultured CD19-positive B-cell tumor cells TMD8 or RS4;11 with Jurkat-CD16a(V158)-NFAT reporter cells and in peripheral blood mononuclear cells.
“In both assays, orelabrutinib slightly enhances, or well retains the [antibody-dependent cellular cytotoxicity] activity of tafasitamab, while ibrutinib consistently suppresses the [antibody-dependent cellular cytotoxicity] function of tafasitamab,” the researchers wrote.
Furthermore, the data suggest ibrutinib has an “off-target effect” on interleukin-2-inducible T-cell kinase (ITK), “which in turn may lead to compromised [antibody-dependent cellular cytotoxicity] activity of tafasitamab,” according to the study’s authors.
However, orelabrutinib is a highly selective Bruton tyrosine kinase (BTK) inhibitor that does not impact ITK, “which confers its ability to enhance or retain the [antibody-dependent cellular cytotoxicity] activity of tafasitamab,” they wrote.
Combining orelabrutinib with tafasitamab and/or lenalidomide led to synergistic tumor lysis activity, with or without the presence of immune effector cells. An in vivo efficacy study of REC-1 xenografts also showed “much improved” tumor growth inhibition with a combination of orelabrutinib, tafasitamab, and lenalidomide compared with use of single agents, according to the study’s authors.
“The highly selective BTK inhibitor orelabrutinib offers an alternative to ibrutinib as a combinatory partner with antibody therapeutics whose mechanism of action is highly dependent on [antibody-dependent cellular cytotoxicity],” the study’s authors wrote. “Confirmation of the synergistic effects of orelabrutinib with tafasitamab and lenalidomide in various preclinical models has provided scientific rationales for testing the combinatory treatment in clinical studies.”
Orelabrutinib, tafasitamab, and lenalidomide combinations are now under evaluation for safety and efficacy in an open-label, single-arm, multicohort phase I study of patients with relapsed or refractory non-Hodgkin lymphoma.
Reference
Zhang H, Liang R, Xu H, et al. Combination of BTK inhibitor orelabrutinib, anti-CD19 antibody tafasitamab, and IMiD lenalidomide for the treatment of B cell malignancies. Abstract 4013. Presented at the American Association of Cancer Research; April 14-19, 2023; Orlando, Florida.