Arvinas Reports Promising Preclinical Data for ARV-393 and Glofitamab Combination in B-Cell Lymphoma
核心洞察
Arvinas presented preclinical data at ASH 2025 showing that the combination of ARV-393 and glofitamab achieved up to 91% tumor growth inhibition in B-cell lymphoma (搜索) models, significantly outperforming either agent alone.
The combination demonstrated complete tumor regression in all mice at higher doses, with mechanistic studies revealing that ARV-393 upregulates CD20 (搜索) expression and enhances immune signaling pathways.
Based on these results, Arvinas plans to initiate a Phase 1 combination clinical trial in diffuse large B-cell lymphoma (搜索) patients in 2026, pursuing a chemotherapy-free treatment approach.
Arvinas announced compelling preclinical data demonstrating enhanced antitumor activity when combining its investigational PROTAC BCL6 degrader ARV-393 with the CD20 (搜索)×CD3 (搜索) bispecific antibody glofitamab in B-cell lymphoma (搜索) models. The data, presented at the 67th American Society of Hematology Annual Meeting in Orlando, Florida, support the company's plans to initiate a combination clinical trial in 2026.
Significant Tumor Growth Inhibition Observed
In humanized high-grade B-cell lymphoma (搜索) cell line-derived xenograft models, the combination therapy demonstrated markedly superior efficacy compared to monotherapy approaches. ARV-393 at 3 mg/kg combined with glofitamab at 0.15 mg/kg achieved 81% tumor growth inhibition with concomitant dosing and 91% with sequential dosing, substantially exceeding the 38% inhibition seen with ARV-393 alone and 36% with glofitamab monotherapy.
At higher ARV-393 doses of 6 mg/kg combined with glofitamab, complete tumor regression was observed in all mice (10/10) with concomitant dosing and in 7 of 8 mice with sequential dosing. This compared favorably to single-agent ARV-393, which achieved regression in 5 of 11 mice, while glofitamab alone produced no tumor regressions.
Mechanistic Insights Support Combination Rationale
RNA sequencing and biomarker analyses revealed the molecular basis for the observed synergy. ARV-393 treatment upregulated CD20 (搜索) expression and genes promoting interferon signaling and antigen presentation, while simultaneously downregulating proliferation-associated gene sets. These collective effects likely contributed to the enhanced antitumor activity when combined with the CD20-targeting bispecific antibody.
"We believe these results underscore the potential for ARV-393 and provide a strong mechanistic rationale for exploring ARV-393 in combination with glofitamab as a chemotherapy-free treatment strategy for patients with diffuse large B-cell lymphoma (搜索)," said Angela Cacace, Ph.D., Chief Scientific Officer at Arvinas.
Addressing Unmet Medical Need in DLBCL
The combination approach aims to address significant treatment gaps in diffuse large B-cell lymphoma (搜索), where patients face limited options after standard therapies fail. Noah Berkowitz, M.D., Ph.D., Chief Medical Officer at Arvinas, emphasized the potential clinical impact: "Despite advances in treatment options, many patients with diffuse large B-cell lymphoma continue to face limited options once standard therapies fail. By pursuing a chemotherapy-free combination approach, we aim to address this significant unmet need and potentially offer patients a more targeted, better-tolerated therapeutic alternative."
Clinical Development Timeline
ARV-393 is currently being evaluated in a Phase 1 clinical trial in patients with relapsed/refractory non-Hodgkin lymphoma (搜索). Arvinas plans to share clinical data from this ongoing trial at a medical congress in 2026. Additionally, the company intends to add a glofitamab combination cohort for DLBCL patients to the existing Phase 1 trial in 2026.
PROTAC Technology Targeting BCL6
ARV-393 represents an investigational, orally bioavailable PROTAC designed to specifically target and degrade B-cell lymphoma (搜索) 6 protein (BCL6), a transcriptional repressor and major driver of B-cell lymphomas. BCL6 regulates over 600 genes during B-cell development, and its deregulated expression in B-cell lymphoma promotes cancer cell survival, proliferation, and genomic instability. PROTAC-mediated degradation has the potential to address the historically undruggable nature of BCL6.