Background: R-CHOP has been widely recognized as effective first-line treatment for DLBCL. However, 30-50% of the patients are either refractory or eventually develop relapsed diseases (r/r DLBCL). The CD19-targeted cytolytic antibody tafasitamab, in combination with immunomodulating drug (IMiD) lenalidomide, has been approved as one of the very few treatment options for transplant-ineligible patients with r/r DLBCL. Tafasitamab is a Fc-enhanced anti-CD19 monoclonal antibody, mediating B cell tumor lysis through ADCC/ADCP activities and direct cytotoxicity. Bruton’s tyrosine kinase (BTK) is a key oncogenic driver in many B cell malignancies. Orelabrutinib is a highly selective BTK inhibitor approved for r/r CLL/SLL and r/r MCL in China. In addition, multiple clinical trials of orelabrutinib are being carried out for the treatment of other B cell lymphomas including the MCD subtype of DLBCL. In this study, we have investigated the potential benefit of combining orelabrutinib with tafasitamab and lenalidomide in pre-clinical B cell tumor models.

Results: ADCC activity of tafasitamab alone or in combination with lenalidomide and orelabrutinib/ibrutinib was measured by co-culturing CD19+ B cell tumor cells TMD8 or RS4;11 with Jurkat-CD16a(V158)-NFAT reporter cells or PBMC. In both assays, orelabrutinib slightly enhances, or well retains the ADCC activity of tafasitamab, while ibrutinib consistently suppresses the ADCC function of tafasitamab. Mechanistically, our data indicate that ibrutinib has an off-target effect on ITK, a key kinase regulating FcR signaling in NK cells, which in turn may lead to compromised ADCC activity of tafasitamab. In contrast, orelabrutinib is a highly selective BTK inhibitor with no effect on ITK, which confers its ability to enhance or retain the ADCC activity of tafasitamab. Combination of orelabrutinib with tafasitamab and/or lenalidomide also leads to synergistic tumor lysis activity, with or without the presence of immune effector cells. In vivo efficacy study of REC-1 xenografts has further demonstrated much improved tumor growth inhibition with combinatory treatment of orelabrutinib, tafasitamab and lenalidomide compared to single agents.

Conclusions: 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 ADCC. 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. An open-label, single-arm, multi-cohort phase I study to evaluate the safety and efficacy of orelabrutinib, tafasitamab and lenalidomide combinations in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL) is ongoing.

Citation Format: Hongjuan Zhang, Ruixia Liang, Haipeng Xu, Xiaorong Li, Renbin Zhao, Jason Bin Zhang, Davy Xuesong Ouyang. Combination of BTK inhibitor orelabrutinib, anti-CD19 antibody tafasitamab, and IMiD lenalidomide for the treatment of B cell malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4013.