Epkinly Cuts DLBCL Progression Risk 51% in First-Line Phase 3, Taking Aim at Polivy

AbbVie and Genmab’s Epkinly cut the risk of disease progression or death by 51% in newly diagnosed diffuse large B-cell lymphoma when added to standard R-CHOP chemotherapy, topline results from the Phase 3 EPCORE DLBCL-2 trial show. The hazard ratio of 0.49 is the strongest treatment effect reported to date among major registrational trials in first-line DLBCL, and it makes Epkinly the first bispecific antibody combination to reach statistical significance in that setting.

The trial (NCT05578976) enrolled roughly 900 patients with newly diagnosed DLBCL and an International Prognostic Index (IPI) score of 2 to 5, randomizing them to subcutaneous epcoritamab plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or to R-CHOP alone. The 51% reduction in progression risk blew past analyst forecasts of a 30% to 35% benefit, and the effect held across high-risk and lower-risk subgroups alike. The combination was generally well tolerated, with side effects consistent with the known profiles of the individual drugs.

How Epkinly Works and Why the Front Line Is the Prize

Epkinly, a CD20xCD3 bispecific T-cell engager dosed by subcutaneous injection, is already approved in the U.S. and more than 65 countries for later-line lymphoma. The mechanism is elegant and off-the-shelf: one arm binds CD20 on the lymphoma B cell, the other binds CD3 on any nearby T cell, physically forcing the T cell to kill the tumor. No CAR-T manufacturing, no apheresis, no weeks-long wait — the patient’s own T cells are recruited on the spot. That convenience profile is exactly why a first-line label is so valuable: DLBCL is a front-loaded disease, and the setting where the most patients can be reached with a fixed-duration, pharmacy-deliverable drug.

A first-line label would put it directly against Roche’s Polivy (polatuzumab vedotin), which won frontline DLBCL approval in April 2023 after cutting progression risk by 27%, and against Incyte’s Monjuvi (tafasitamab), whose own first-line combination met its primary endpoint in January. Polivy generated about $972 million in the first half of 2026, a measure of the franchise Epkinly is now contesting. On the topline numbers, a 51% reduction versus Polivy’s 27% is not a marginal edge — though cross-trial comparisons are hazardous, and Polivy’s POLARIX enrolled a different risk mix. The drug belongs to the CD20xCD3 bispecific class that has reshaped the lymphoma treatment field.

What It Means for the Trade

Genmab shares jumped about 11% on the news, closing at $38.48 on Monday. AbbVie closed at $265.76, up about 1%. The asymmetry makes sense: Genmab gets the bigger re-rate because epcoritamab is a core growth driver for a mid-cap biotech, while for AbbVie this is one of several pipeline wins needed to offset the Humira erosion story.

The readout is a reset for a program that has had a choppy year. In January, Epkinly monotherapy missed its overall survival endpoint in the relapsed/refractory EPCORE DLBCL-1 trial; in June, the EPCORE DLBCL-4 combination with lenalidomide read out positive in the same relapsed/refractory population. The first-line win is the bigger prize, with TD Cowen analysts pegging Epkinly’s peak sales potential at $3 billion on a first-line label.

AbbVie and Genmab say they will take the data to global regulators to determine next steps and plan to present a fuller analysis at an upcoming medical meeting. Watch the filing timeline: a near-term submission could put an approval decision into 2027, and every quarter of head start matters in a market where Polivy’s contracting relationships with treatment centers are already embedded.

Risks and What Could Go Wrong

The first is commercial, not clinical. EPCORE DLBCL-2 tested epcoritamab plus R-CHOP against R-CHOP alone — there is no head-to-head against Polivy plus R-CHOP, so the 51-versus-27 comparison is across different trials. Payers and guideline panels will want to see the full dataset, including how the arms balanced on refractory subtypes, before conceding superiority.

Second, tolerability details matter at this class level. Bispecific T-cell engagers carry cytokine-release and infection risks, and adding one to full-dose R-CHOP raises questions about CRS management, dose-density, and hospitalization rates that topline language (“generally well tolerated”) does not answer. If the full analysis shows meaningfully higher toxicity or treatment discontinuations, adoption will slow regardless of the hazard ratio.

Third, the field moves. Polivy is not standing still, CAR-T is being explored earlier in the line, and fixed-duration combinations are becoming a crowded thesis. A three-way fight for the same front-line patients — Epkinly, Polivy, Monjuvi — with overlapping mechanisms of addition to R-CHOP means the winner may be decided by detail data, sequencing strategy, and price, not topline hazard ratios.

What to watch next is the filing timeline and whether the fixed-duration combination can convert its head-to-head edge over Polivy into share in a first-line market where R-CHOP has been the backbone for two decades.

Source: AbbVie and Genmab press release