Abstract 1655: ARV-393, a PROTAC B-cell lymphoma 6 (BCL6) degrader, combined with biologics or small molecule inhibitors (SMIs) induces tumor regressions in diffuse large B-cell lymphoma (DLBCL) models

Abstract BCL6 is a preclinically validated oncogenic driver of DLBCL historically considered to be undruggable. ARV-393, a PROteolysis TArgeting Chimera (PROTAC) degrader, directly binds an E3 ubiquitin ligase and BCL6 to induce 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 (CDX and PDX) DLBCL models. ARV-393 monotherapy is being evaluated in a phase 1 trial (NCT06393738) in patients with non-Hodgkin lymphoma, including DLBCL. Given the heterogeneity and multiple resistance mechanisms of DLBCL and that BCL6 regulates hundreds of genes linked to oncogenesis and resistance, BCL6 degradation has the potential for broad drug combinability. For example, CREBBP/EP300 and BCL6 have opposing transcriptional activities and BCL6 degradation may prevent CD20 downregulation by restoring CREBBP/EP300 chromatin access, supporting combination with anti-CD20 biologics; cooperation of EZH2 with the BCL6 repressor complex supports combining with tazemetostat (taz). Thus, we assessed the activity of ARV-393 in combination with biologics or SMIs based on potential complementary mechanistic roles. ARV-393 was administered in combination with clinically relevant doses of the standard of care (SOC) biologics rituximab, tafasitamab (tafa) and polatuzumab to mice bearing SU-DHL-4 CDX, representing a high-grade B-cell lymphoma (HGBCL, with MYC, BCL2 and BCL6 rearrangements). ARV-393 was also combined with investigational SMIs of EZH2 (taz), BCL2 (venetoclax) and BTK (acalabrutinib), in HGBCL or aggressive CDX models SU-DHL-6 (EZH2mut), OCI-Ly1 (BCL2+) and activated B-cell (ABC)-like OCI-Ly10 (MYD88 mut), respectively. ARV-393 combined with SOC biologics resulted in superior tumor growth inhibition (TGI) compared with monotherapy, with complete tumor regressions in 9/9 mice when combined with rituximab, 4/10 with polatuzumab, and 10/10 with tafa (vs 55% TGI tafa + lenalidomide). ARV-393 also produced tumor regressions in 10/10 mice when combined with taz, 10/10 with venetoclax, and 10/10 with acalabrutinib. In a SU-DHL-6 model, MYC, EZH2 and BCL2 protein levels were increased 56%, 66% and 12%, respectively, with ARV-393 alone vs vehicle, but were decreased 75%, 80% and 96% vs vehicle, with greater BCL6 degradation (65% vs 87%) when combined with taz. Studies to examine the molecular mechanisms underlying the combination synergies are ongoing. ARV-393 demonstrates synergistic antitumor activity, including complete regressions, in combination with SOC agents and select SMIs in high grade and aggressive DLBCL models. These findings support future clinical investigation of ARV-393 in combination with other therapies for DLBCL. Citation Format: Anna Van Acker, Lynn DeCarr, Sarah Eaton, Dan Sherman, Elizabeth Bortolon, Mark Bookbinder, Jennifer Pizzano, Morena Scopel, William Corwin, Ignacio Juncadella, Yongqing Huang, Ram Lingamaneni, Stephanie Renzullo, Jennifer Cantley, XiaoZhe (Janet) Wang, Ian Taylor, Sean Landrette, Sheryl M. Gough. ARV-393, a PROTAC B-cell lymphoma 6 (BCL6) degrader, combined with biologics or small molecule inhibitors (SMIs) induces tumor regressions in diffuse large B-cell lymphoma (DLBCL) models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1655.