Background: Despite significant progress made in the treatment of non-Hodgkin lymphoma (NHL) through advancements with immunochemotherapy, autologous stem cell transplantation, chimeric antigen receptor T-cell therapies, bispecific antibodies, and other targeted therapies, many patients ultimately experience disease progression or relapse. Thus, there is a need for agents with novel mechanisms of action and combination strategies that can improve disease-free survival and overall survival without increasing toxicity.

BCL6 is a master transcriptional regulator that controls key processes during B-cell lymphomagenesis. Deregulated BCL6, as a result of genomic aberrations of the BCL6 gene or of the genes encoding factors that regulate BCL6, has been implicated as an oncogenic driver in NHL. BCL6 regulates hundreds of genes linked to oncogenesis and therapeutic resistance. Given the heterogeneity of disease and resistance mechanisms in relapsed NHL, targeting BCL6 offers a novel and complementary mechanism of action with the potential for broad drug combinability.

ARV-393, a PROteolysis TArgeting Chimera (PROTAC) degrader, forms a complex with an E3 ubiquitin ligase and BCL6, inducing ubiquitination of BCL6 and its subsequent proteasomal degradation. ARV-393's iterative activity overcomes rapid resynthesis of BCL6, resulting in potent, single-agent activity and tumor regressions in many cell- and patient-derived xenograft models of diffuse large B-cell lymphoma (DLBCL). ARV-393 monotherapy is currently being evaluated in a phase 1 trial (NCT06393738) in patients with NHL, including DLBCL. ARV-393 demonstrated synergistic antitumor activity, including complete regressions, in combination with standard-of-care agents and investigational small-molecule inhibitors in HGBCL and aggressive DLBCL cell line–derived xenograft (CDX) models. Here we demonstrate that the broad preclinical combinability of ARV-393 extends to the CD20×CD3 bispecific antibody glofitamab.

Methods: A CD34+ humanized WSU-DLCL2 HGBCL CDX model was used to evaluate ARV-393 (3 or 6 mg/kg) in combination with glofitamab (0.15 mg/kg). Concomitant (initiating ARV-393 and glofitamab treatment together) and sequential (initiating glofitamab after 7 days of ARV-393 treatment) dosing schedules were evaluated. RNA-sequencing and pathway biomarker analyses were performed to identify potential mechanisms underlying beneficial combinability.

Results: ARV-393 showed combinatorial antitumor activity with glofitamab. ARV-393 at a low dose (3 mg/kg) combined with glofitamab resulted in substantially greater tumor growth inhibition (TGI) with concomitant dosing (81%) or sequential dosing (91%) compared with single-agent ARV-393 (38%) or glofitamab (36%). ARV-393 at a higher dose (6 mg/kg) in combination with glofitamab yielded a deeper TGI of 106% with concomitant dosing and 107% with sequential dosing vs 99% TGI with single-agent ARV-393; an increase in tumor regressions was also observed with concomitant dosing (10/10 mice) and sequential dosing (7/8 mice) vs single-agent ARV-393 (5/11 mice) or glofitamab (0/11 mice). RNA-sequencing and pathway biomarker analyses provided mechanistic insight into the observed synergistic activity and suggest ARV-393 enhances CD20 expression, interferon pathway activity, and antigen presentation, which likely collectively contribute to combinatorial activity.

Conclusions: ARV-393 demonstrated combinatorial antitumor activity with glofitamab as evidenced by deeper TGI than single-agent ARV-393 or glofitamab and by an increase in tumor regressions with both concomitant and sequential dosing of the combination. These findings suggest mechanistic synergies between BCL6 degradation with ARV-393 and T-cell engagement through a CD20-targeted bispecific antibody and support clinical investigation of this chemotherapy-free combination in patients with DLBCL.

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2025
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