Epcoritamab plus R-CHOP cuts DLBCL progression risk by 51% in Phase 3

Genmab and AbbVie have reported positive topline results from the Phase 3 EPCORE DLBCL-2 trial, in which the subcutaneously administered bispecific antibody epcoritamab, added to standard chemotherapy regimen R-CHOP, reduced the risk of disease progression or death by 51% compared with R-CHOP alone in newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients with an International Prognostic Index score of 2 to 5 (hazard ratio 0.49, 95% CI 0.36–0.67; p less than 0.0001).

The companies describe the outcome as the first statistically significant PFS result from a Phase 3 trial of a bispecific antibody combination in the frontline DLBCL setting. The safety profile of the combination was reported as generally well tolerated and consistent with those previously seen for each agent individually. Full data have not yet been disclosed and will be submitted for presentation at a future medical meeting.

Trial design and what the numbers mean

EPCORE DLBCL-2 is a global, open-label, randomised, multi-centre study (NCT05578976) that enrolled patients across multiple large B-cell lymphoma subtypes. Participants were randomised 2:1 to receive six cycles of epcoritamab plus R-CHOP followed by two cycles of epcoritamab alone, or six cycles of R-CHOP followed by two cycles of rituximab. The primary endpoint was PFS in the highest-risk IPI 3–5 subgroup; the key secondary endpoint extended the analysis to the full IPI 2–5 population. The 51% risk reduction cited by the companies applies to the primary endpoint population, with a closely aligned hazard ratio of 0.49 (95% CI 0.35–0.69; p less than 0.0001) also reported for that group separately.

Genmab chief executive Jan van de Winkel said the results "have the potential to reshape the frontline treatment landscape," while Gilles Salles, Chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center and an investigator on both EPCORE DLBCL-2 and the original study that established R-CHOP as standard of care roughly 25 years ago, described the 51% risk reduction as "clinically meaningful and highly relevant to everyday practice."

Market context and competitive read-across

DLBCL is the most prevalent subtype of non-Hodgkin lymphoma, representing approximately 25–30% of all NHL cases globally and around 25,000 new diagnoses annually in the United States. R-CHOP has been the backbone of frontline treatment for approximately two decades, and multiple attempts to improve on it in the first-line setting have failed to meet PFS endpoints in randomised trials, making the EPCORE DLBCL-2 result notable.

The bispecific antibody class has made significant inroads in relapsed or refractory DLBCL. Epcoritamab already holds regulatory approvals for relapsed or refractory DLBCL and follicular lymphoma in more than 65 countries under the brand names EPKINLY (US and Japan) and TEPKINLY (EU). Mosunetuzumab, another CD20xCD3 bispecific from Roche, is approved in relapsed or refractory follicular lymphoma, and glofitamab has approval in relapsed or refractory DLBCL. Moving into the frontline with a randomised Phase 3 win represents a meaningful step up the treatment pathway for the class as a whole.

Genmab and AbbVie said they will now engage global regulatory authorities to determine next steps. No timelines for regulatory submissions were provided in the topline announcement. Investors and clinicians will look for the complete dataset, including overall survival data, quality-of-life outcomes, and subgroup analyses by cell-of-origin and molecular subtype, before forming firm views on whether epcoritamab plus R-CHOP can supplant R-CHOP as the new standard of care in high-risk, newly diagnosed DLBCL.