Epcoritamab (Epkinly) Improves PFS But Fails To Show Unadjusted OS Benefit In Phase III EPCORE DLBCL‑1

Primary results from the global, randomised Phase III EPCORE DLBCL‑1 trial (EudraCT 2020‑003016‑27), presented at the European Hematology Association (EHA) 2026 Congress, show that subcutaneous epcoritamab (Epkinly) improved progression‑free survival (PFS) but did not produce a statistically significant overall survival (OS) benefit in relapsed/refractory large B‑cell lymphoma (R/R LBCL).

Trial Design and Population

The trial randomised 483 patients who were either ineligible for autologous stem‑cell transplant (ASCT) or had relapsed after ASCT and had received ≥1 prior line of therapy. Patients were assigned to single‑agent Epkinly (a CD3×CD20 bispecific administered subcutaneously) or investigator’s choice chemoimmunotherapy (CIT: rituximab plus gemcitabine/oxaliplatin or rituximab plus bendamustine). Dual primary endpoints were PFS and OS, with at least one required to be met.

Key Efficacy Results

After median follow‑up of 43.2 months (Epkinly) and 42.3 months (CIT):

• PFS: Epkinly met the PFS endpoint with HR 0.74 (95% CI 0.60–0.92; p=0.0059). The 24‑month PFS was 30% for Epkinly versus 13% for CIT.
• ORR and CR: Objective response rates were similar (51% Epkinly vs 48% CIT), but Epkinly produced a higher complete response rate (38% vs 26%).
• Duration Of Response & Time To Next Treatment: Median duration of complete response was not reached with Epkinly vs 10.8 months with CIT; time to next treatment was 6.6 vs 4.3 months.
• OS: Unadjusted overall survival did not differ significantly (HR 0.96; 95% CI 0.77–1.20).

Confounders And Post‑Hoc Analysis

Investigators cited two major confounders that likely affected the OS read: (1) enrolment overlapped substantially with the Covid‑19 pandemic (Omicron wave), with Covid‑related deaths of 9% in the Epkinly arm versus 3% in CIT; and (2) an imbalance in effective post‑progression therapies—such as other bispecifics, CAR T‑cell therapy, or transplant—favoring the CIT arm (31% vs 6%). A post‑hoc analysis adjusting for both factors shifted the OS HR to 0.76 (95% CI 0.59–0.99), favoring Epkinly.

Safety

Safety signals were nuanced. Crude rates of grade 3–4 infections were higher with Epkinly (30% vs 12%), and grade 5 treatment‑emergent adverse events were 17% vs 6% with CIT. Investigators attributed these differences largely to much longer exposure in the Epkinly arm (mean exposure 11 months vs 2 months) and to pandemic impacts rather than intrinsic toxicity. On an exposure‑adjusted basis, grade 3–4 infections were comparable (4.3 vs 4.9 events per 100 patient‑months). Febrile neutropenia was reported less frequently with Epkinly (2% vs 5%).

Regulatory And Clinical Implications

EPCORE DLBCL‑1 is the first randomised Phase III trial to show a single‑agent CD3×CD20 bispecific antibody improving PFS over CIT in R/R LBCL—data that could support moving Epkinly into the second‑line setting. However, because only one co‑primary endpoint was met, Genmab plans to discuss next steps with global regulators. The path to broader approval is uncertain, particularly given the FDA’s August 2025 draft guidance emphasizing OS as both an efficacy and safety endpoint and recent precedent: in 2025 the FDA declined approval of Roche’s Columvi (glofitamab) plus chemotherapy in a similar second‑line population.

Other Notes And Commercial Outlook

Epkinly’s gemcitabine/oxaliplatin combination (from Phase Ib/II EPCORE NHL‑2) is listed as an NCCN‑preferred option for CAR T‑ineligible R/R DLBCL despite not having a formal FDA indication in that combination. The agent is being evaluated across multiple haematologic malignancies. Analyst consensus from GlobalData projects global sales of approximately $2.795 billion by 2032.

Bottom Line: Epkinly delivers a meaningful PFS improvement and deeper complete responses versus chemoimmunotherapy in a difficult‑to‑treat population, but unadjusted OS was not superior. Regulatory decisions will hinge on interpretation of pandemic‑era confounders, post‑progression therapy imbalances and exposure‑adjusted safety data.