In a humanized high-grade B‑cell lymphoma xenograft model, ARV‑393 combined with glofitamab delivered 81% tumor growth inhibition with concomitant dosing and 91% with sequential dosing (ARV‑393 then glofitamab), compared with 38% for ARV‑393 alone and 36% for glofitamab alone. At a higher ARV‑393 dose, complete tumor regressions occurred in 10/10 mice with concomitant dosing and 7/8 with sequential dosing, versus 5/11 for ARV‑393 monotherapy and 0/11 for glofitamab alone.
Arvinas has used these preclinical findings, presented at ASH, to justify a chemotherapy‑free combination cohort in its ongoing Phase 1 trial of ARV‑393 in relapsed/refractory non‑Hodgkin lymphoma, with a diffuse large B‑cell lymphoma focus, targeted to initiate in 2026. The company also plans to share first clinical data from the ARV‑393 monotherapy Phase 1 in 2026. The mechanistic rationale centers on BCL6 degradation upregulating CD20 and antigen presentation pathways, potentially enhancing the activity of a CD20×CD3 T‑cell engager such as glofitamab.
Strategically, this is an expansion play that leans into two converging trends in aggressive lymphoma: chemo‑free regimens and rational pairing of immune engagers with agents that counter antigen escape and proliferative signaling. DLBCL treatment has shifted toward bispecifics and cellular therapies, but resistance and tolerability remain limiting. If ARV‑393 can reproducibly elevate CD20 and reshape interferon signaling in patients, the combination could address a known failure mode for CD20‑directed therapies. The stronger effect seen with sequential dosing suggests the development plan may emphasize schedule optimization, a practical differentiator relative to empiric triplets now populating later‑line studies.
For sites and CROs, the operational footprint will look more like an immunotherapy study than a small‑molecule trial, with all the associated infrastructure: step‑up dosing, CRS/ICANS preparedness, premedication management, and infusion chair capacity. Layering an oral degrader onto a bispecific backbone adds adherence and drug‑interaction monitoring, biopsy logistics for pharmacodynamic readouts, and potentially more intensive early‑cycle assessments if sequencing is tested. The biomarker plan becomes central: serial measurement of CD20 expression and interferon‑responsive signatures could support adaptive dosing and cohort gating, but it will require coordinated tissue acquisition and rapid analytics. Safety run‑ins will likely be mandatory, given the unknown clinical toxicity profile of a BCL6 degrader combined with T‑cell activation; overlapping cytopenias and infection risk will draw regulatory scrutiny, especially if inpatient monitoring is required during initial glofitamab administration.
The move also signals the need for external alignment. Glofitamab is owned by Roche/Genentech, so supply and pharmacovigilance agreements will be prerequisites, and timelines often hinge on these partnerships. Manufacturing and CMC readiness for a chronic oral degrader will matter if the combination advances; any requirement to modulate glofitamab dosing to manage CRS could complicate comparability to labeled regimens and study feasibility across geographies.
What to watch next is straightforward: initial ARV‑393 monotherapy data in 2026 for safety, exposure, early response, and evidence of target engagement in patient tumors. Study design details for the combination cohort will be telling—specifically whether sequential dosing is prospectively tested, how step‑up dosing is synchronized, and what inpatient monitoring is mandated. Competitive context will tighten as bispecific combinations with lenalidomide or targeted agents mature; the bar is clinical additivity without a material increase in CRS or infections. If the CD20‑upregulation signal translates in humans, the approach could extend beyond glofitamab to other CD20 engagers, but the translational risk from xenograft models remains high, making the first clinical readout the gating event.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
