Phase 1 study of ARV-393, a PROTAC BCL6 degrader, as monotherapy in patients with advanced non-Hodgkin lymphoma (NHL) or combined with glofitamab in patients with diffuse large B-cell lymphoma (DLBCL).

TPS7103 Background: Despite recent advancements in NHL therapies, many patients experience disease progression or relapse. Agents with novel mechanisms of action and combination strategies are needed to improve clinical outcomes. B-cell lymphoma 6 (BCL6) is a master transcriptional regulator of immune cells, particularly of germinal center B cells, and an established oncogenic driver in NHL. ARV-393 is an oral PROteolysis TArgeting Chimera (PROTAC) BCL6 degrader that binds an E3 ubiquitin ligase and BCL6 to induce ubiquitination of BCL6 and its subsequent proteasomal degradation. ARV-393 monotherapy potently inhibited tumor growth and induced tumor regressions across NHL cell-derived xenograft (CDX) and patient-derived xenograft models, including models of DLBCL, transformed follicular lymphoma, and nodal T-follicular helper cell lymphoma (nTFHL). Furthermore, administration of ARV-393 with a CD20×CD3 bispecific antibody, glofitamab, demonstrated combinatorial antitumor activity in a humanized high-grade B-cell lymphoma CDX model, inducing deeper tumor growth inhibition and increased tumor regressions vs either monotherapy. These preclinical findings demonstrated single-agent ARV-393 antitumor activity across NHL subtypes and suggested mechanistic synergy with glofitamab, supporting clinical investigation of monotherapy in NHL and this chemotherapy-free combination in patients with DLBCL. Methods: This global, multicenter, open-label, first-in-human, phase 1 dose escalation and optimization/expansion study (NCT06393738) is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ARV-393 as monotherapy in relapsed or refractory (R/R) NHL or in combination with glofitamab in R/R DLBCL, with a primary objective of determining provisional doses for further exploration. Patients eligible for ARV-393 monotherapy are adults with confirmed R/R B-cell NHL who previously received ≥2 lines of systemic therapy (including rituximab), or nTFHL who previously received standard of care therapy. Patients eligible for ARV-393 in combination with glofitamab are adults with pathologically confirmed R/R DLBCL, DLBCL not otherwise specified, or large B-cell lymphoma arising from follicular lymphoma who were treated with ≥2 prior lines of systemic therapy. ARV-393 will be administered orally once daily in 28-day cycles alone or in combination with intravenous glofitamab during 21-day cycles. Approximately 255 patients will be enrolled across study cohorts. As of January 2026, enrollment is ongoing.