Bispecific antibody epcoritamab shows high response in untreated follicular lymphoma

Adding the bispecific antibody epcoritamab to a standard chemotherapy-free pairing produced tumour responses in nearly every previously untreated follicular lymphoma patient in an early trial: in the EPCORE NHL-2 cohort, 39 of 41 patients — 95% — responded [s1]. But this was a single-arm study with no comparison group, so it cannot show that adding epcoritamab beats the two-drug backbone of rituximab and lenalidomide on its own, which already produces high response rates in this disease [s1].

Follicular lymphoma is a slow-growing cancer of B cells that is treatable but generally considered incurable, marked by repeated cycles of response and relapse over many years. First-line treatment has increasingly moved away from chemotherapy toward the combination of the anti-CD20 antibody rituximab and the immune-modulating drug lenalidomide — an approach that spares patients cytotoxic chemotherapy while still controlling disease [s1]. The open question is whether deeper, longer-lasting remissions can be reached by adding a newer class of drug on top.

Epcoritamab is a CD3×CD20 bispecific antibody: one arm grabs the CD20 marker on the lymphoma cell, the other grabs the CD3 receptor on a T cell, physically bridging the two so the patient's own immune cells attack the cancer [s1]. It works by a mechanism related to the T-cell-engaging antibodies now replacing chemotherapy in some leukaemias. EPCORE NHL-2 tested it, given by subcutaneous injection, added to rituximab and lenalidomide as a first treatment [s1].

What they did

This was an open-label, multicentre phase 1/2b trial — early-stage research designed to gauge activity and safety, not a definitive comparison [s1]. The first-line follicular lymphoma cohort enrolled 41 patients between September 2021 and May 2022, all of whom received at least one dose [s1]. Rituximab was given weekly in the first cycle and then every four weeks; oral lenalidomide 20 mg daily on days 1 to 21 of the first 12 cycles; and epcoritamab worked up through a two-step priming schedule — a 0.16 mg dose, then 0.8 mg, then full 48 mg doses — to reduce the risk of an over-brisk immune reaction, continued for up to two years [s1]. The primary endpoint was the overall response rate judged by the investigators against standard lymphoma criteria [s1]. The trial is registered as NCT04663347 and is closed to new participants [s2].

The design carries the key caveat plainly: with a single arm of 41 patients and no randomised control, the trial measures how often the three-drug combination worked, not whether the third drug added anything the other two would not have delivered [s1].

What it showed

At a median follow-up of 35.9 months, the overall response rate was 95% (95% confidence interval, 84 to 99), with 39 of 41 patients responding [s1]. That is a high number — but it should be read against the fact that rituximab and lenalidomide alone already produce response in the large majority of patients with untreated follicular lymphoma, which is precisely why a single-arm result cannot isolate epcoritamab's contribution [s1]. The trial's authors describe the combination as a promising approach that warrants further analysis to establish its role, language that matches the strength of the evidence rather than overselling it [s1].

The cost side

The added antibody brought meaningful toxicity. The most common grade 3 or 4 adverse events were low white-cell counts (neutropenia, 49%), infections (29%), COVID-19 (15%) and raised liver enzymes (12%) [s1]. Serious adverse events occurred in 71% of patients, including cytokine release syndrome — the immune-overactivation reaction characteristic of T-cell-engaging drugs — in 32% [s1]. Most consequentially, three patients (7%) died of causes the investigators attributed to treatment: septic shock, a rare brain infection called progressive multifocal leukoencephalopathy, and COVID-19 [s1]. In a disease many patients live with for years on gentler regimens, three treatment-related deaths among 41 people is not a footnote; it is central to weighing this combination [s1].

What to watch

EPCORE NHL-2 shows that epcoritamab can be combined with the standard chemotherapy-free backbone and that responses are frequent, but it leaves the decisive question — does adding it lengthen remission or life beyond rituximab-lenalidomide alone, and at what cost — for the randomised trials that must follow [s1]. The trial was funded by Genmab and AbbVie, which develop epcoritamab [s1]. For now, a 95% response rate in 41 patients is an encouraging early signal, not evidence that a new standard has arrived; the toxicity, including the treatment-related deaths, means the eventual verdict will hinge on benefit that a controlled trial has yet to demonstrate.

Sources

• [s1] Epcoritamab with rituximab and lenalidomide as first-line treatment for follicular lymphoma (EPCORE NHL-2): an open-label, multicentre, phase 1/2b trial. The Lancet Haematology. 28 August 2026. doi:10.1016/S2352-3026(26)00198-5.
• [s2] ClinicalTrials.gov. A Trial of Epcoritamab (GEN3013; DuoBody-CD3xCD20) in Combination With Other Therapies in Subjects With B-cell Non-Hodgkin Lymphoma (EPCORE NHL-2, NCT04663347). U.S. National Library of Medicine.