Abstract B170: The in vitro anti-tumor activity of the multi-kinase inhibitor nemtabrutinib (ARQ-531, MK-1026) is seen across multiple B-cell lymphoma subtypes, only partially overlapping with what achieved by single BTK inhibition

Abstract

Abstract Background. Nemtabrutinib is a reversible, ATP competitive tyrosine kinase inhibitor of BTK and of several other kinases, including LYN and MEK1 (Reiff et al, Cancer Discov 2018). Nemtabrutinib has shown preclinical and clinical activity in chronic lymphocytic leukemia (CLL), also against tumors bearing mutations affecting the C481 amino acid of BTK (Reiff et al, Cancer Discov 2018; Eradat et al, ICML 2023), which is commonly mutated in patients treated with 1st and 2nd generation inhibitors such as ibrutinib, acalabrutinib, zanubrutinib (Thompson & Tam, Blood 2023). Based on these data, a phase 3 trial is comparing the drug against chemo-immunotherapy in untreated-CLL patients (NCT05624554). Phase 1/2 studies are currently exploring nemtabrutinib in various B-cell lymphomas as single-agent (NCT05673460, NCT04728893) and combined with the ROR1-targeting antibody drug conjugate zilovertamab vedotin (NCT05458297). Due to the ability of nemtabrutinib to block multiple kinases, we exposed a large series of lymphoma cell lines to nemtabrutinib to understand the lymphomas that might most benefit. Methods. Nemtabrutinib (MedChemExpress) was assessed for its anti-proliferative activity at 72h across 54 cell lines, comprising germinal-center B-cell like (GCB) DLBCL (n.=18), activated B-cell like (ABC) DLBCL (n.=8), mantle cell lymphoma (MCL) (n.=10), marginal zone lymphoma (MZL) (n.=6), CLL (n.=2), plus other two derived from B- and eight from T-cell (n.=8) lymphomas. Results. The median IC50 for nemtabrutinib was 1.4 µM (95%CI, 0.8-2.3 µM) across all 54 lymphoma cell lines tested. Higher activity was found in B (median-IC50, 1.1 µM) compared to T (median IC50, 22.6 µM) cell lymphomas. Strong anti-lymphoma activity was observed in CLL cell lines (median IC50, 389 nM), MCL (median IC50, 627 nM), in one primary mediastinal B cell lymphoma (815 nM) and one canine diffuse large B-cell lymphoma cell line (389 nM). No difference was seen between ABC (median IC50, 1 µM) and GCB (median IC50, 1.2 µM) DLBCL. In DLBCL, nemtabrutinib anti-tumor activity was not affected by the presence of inactive TP53, BCL2 and/or MYC translocations. Taking advantage of publicly available ibrutinib data, we observed that nemtabrutinib and the 1st generation BTK inhibitor behaved similarly across 45 lymphoma cell lines (Pearson correlation r=0.5, P=0.001), especially in MCL (r=0.8, P=0.005) and ABC-DLBCL (r=0.75, P=0.039), but not in GCB-DLBCL, in which only nemtabrutinib was active. Further analyses integrating baseline transcriptome and mutational data are underway. Conclusions. Nemtabrutinib showed anti-tumor activity across B-cell lymphomas, higher in some histotypes (including MCL, CLL). The pattern of anti-tumor activity was only partially overlapping by what achieved by the BTK inhibitor ibrutinib: while MCL and ABC-DLBCL responded similarly, activity in GCB-DLBCL was seen only with nemtabrutinib. Citation Format: Giulio Sartori, Filippo Spriano, Luciano Cascione, Chiara Tarantelli, Alberto J. Arribas, Luca Aresu, Davide Rossi, Giovanna Damia, Massimo Broggini, Francesco Bertoni. The in vitro anti-tumor activity of the multi-kinase inhibitor nemtabrutinib (ARQ-531, MK-1026) is seen across multiple B-cell lymphoma subtypes, only partially overlapping with what achieved by single BTK inhibition [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B170.