On April 28, 2025 Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company working to develop a new class of drugs based on targeted protein degradation, reported data from preclinical combination studies of ARV-393, the company’s investigational PROteolysis TArgeting Chimera (PROTAC) B-cell lymphoma 6 protein (BCL6) degrader (Press release, Arvinas, APR 28, 2025, View Source [SID1234652219]). BCL6 is a transcriptional repressor protein and a known driver of B-cell lymphomas. Data demonstrated synergistic antitumor activity, including complete regressions, in combination with standard of care (SOC) chemotherapy, SOC biologics, and investigational oral small molecule inhibitors (SMIs) in high grade B-cell lymphoma (HGBCL) and aggressive diffuse large B-cell lymphoma (DLBCL) models. The results from these preclinical studies were shared in a poster presentation at the 2025 American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting in Chicago, Illinois.
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Key findings from the studies included:
ARV-393 in combination with SOC chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]), induced significantly greater tumor growth inhibition compared with rituximab, CHOP, R-CHOP, or ARV-393 alone, with complete tumor regressions in all mice treated with the ARV-393 and R-CHOP combination.
ARV-393 in combination with SOC biologics targeting CD20 (rituximab), CD19 (tafasitamab), or CD79b (polatuzumab vedotin) resulted in tumor regressions and demonstrated significantly stronger tumor growth inhibition compared with each agent alone.
In preclinical models, ARV-393 increased CD20 expression, providing additional support for the exploration of combinations with CD20-targeted agents and in the context of low or loss of CD20 expression.
ARV-393 in combination with investigational small molecule inhibitors targeting clinically validated oncogenic drivers of lymphoma, such as BTK (acalabrutinib), BCL2 (venetoclax), or EZH2 (tazemetostat), resulted in superior tumor growth inhibition compared with each agent alone, with tumor regressions in all mice treated with the combinations.
"Given that combination regimens are the foundation of lymphoma treatment, we are encouraged by the strength of these preclinical combination data, which demonstrate complete tumor regressions in aggressive lymphoma models," said Noah Berkowitz, M.D., Ph.D., Chief Medical Officer at Arvinas. "We believe these preclinical data demonstrate potential for broad combinability of ARV-393 and provide a compelling rationale for considering combination strategies as we work to bring forward new therapeutic options for lymphoma patients."
A Phase 1 study of ARV-393 is enrolling patients with relapsed/refractory non-Hodgkin lymphoma, including DLBCL (NCT06393738).
Additional detail on the ARV-393 data presentation at AACR (Free AACR Whitepaper) 2025:
Poster Title: ARV-393, a PROteolysis TArgeting Chimera (PROTAC) BCL6 Degrader, Combined With Biologics or Small-Molecule Inhibitors Induces Tumor Regressions in Diffuse Large B-Cell Lymphoma Models
Abstract: 1655
Session Title: Degraders and Glues 2
Session Type: Experimental and Molecular Therapeutic
Location: Poster Section 18
Poster Board Number: 15
Date: Monday, April 28, 2025
Lecture Time: 9:00 a.m. – 12:00 p.m. CT
About ARV-393
ARV-393 is an investigational, orally bioavailable PROteolysis TArgeting Chimera (PROTAC) designed to degrade B-cell lymphoma 6 protein (BCL6), a transcriptional repressor and major driver of B-cell lymphomas. During B-cell development, tightly controlled BCL6 protein expression regulates >600 genes to facilitate rapid B-cell proliferation and tolerance of somatic hypermutation and gene recombination for antibody generation. Deregulated BCL6 expression is common in B-cell lymphoma and promotes cancer cell survival, proliferation, and genomic instability. PROTAC-mediated degradation has the potential to address the historically undruggable nature of BCL6. ARV-393 is currently in a Phase 1 clinical trial in patients with relapsed/refractory non-Hodgkin lymphoma.