Genmab and AbbVie’s epcoritamab fails in phase 3 lymphoma study

Before the EPCORE DLBCL-1 readout, epcoritamab had already secured market access in multiple regions as a treatment for heavily pretreated lymphoma. In the United States, the FDA granted accelerated approval for epcoritamab, under the brand name Epkinly, in relapsed or refractory DLBCL after two or more lines of therapy based on response rates and durability from earlier single-arm studies. In the European Union, the European Commission granted conditional marketing authorization for the same indication. 

Although epcoritamab was granted accelerated and conditional approval, this phase 3 trial was designed to determine whether that activity translated into a survival advantage over existing treatments, a bar the drug did not clear as monotherapy.

The trial readout and what AbbVie and Genmab make of it

In the phase 3 EPCORE DLBCL-1 trial, epcoritamab was tested as a monotherapy in adults with relapsed or refractory DLBCL who were ineligible for more intensive therapies. The global study enrolled 483 patients, most of whom (73%) had already received two or more prior lines of therapy, a heavily pretreated population.

On the primary endpoint of overall survival (OS), the study fell short as epcoritamab did not deliver a statistically significant survival advantage versus standard regimens, with a ratio near parity. That miss is what made the headline, but the secondary efficacy signals were more nuanced according to AbbVie and Genmab. 

The partners reported a 26% reduction in risk of progression or death (PFS) with epcoritamab, along with higher complete response rates, longer durations of response, and delayed time to next therapy in the bispecific arm. These measures reflect deeper disease control in some patients, even if it didn’t translate to longer survival in the overall trial population.

In public comments, both companies have chosen to highlight these benefits. AbbVie described the PFS improvement and other endpoint gains, calling this the first phase 3 demonstration of PFS benefit for a CD3xCD20 bispecific monotherapy, and said it will consult with global regulatory authorities on next steps. Genmab similarly underscored the secondary outcomes, particularly complete responses and duration of response, as evidence that epcoritamab remains active in DLBCL and is worth exploring further. 

It is unsurprising that AbbVie and Genmab have emphasised the secondary efficacy signals, given that overall survival was the trial’s primary endpoint and the one it failed to meet. The data suggest epcoritamab can achieve disease control in heavily pretreated patients, but that this activity was not sufficient to translate into a survival benefit at the population level.

What’s next for epcoritamab

The bar for new therapies in relapsed or refractory DLBCL has risen in recent years. Chimeric antigen receptor (CAR) T-cell therapies have moved earlier in the treatment sequence, while bispecific antibodies and other targeted approaches have expanded the pool of post-relapse options. This means that patients enrolled in late-line trials today are far more likely to receive multiple therapies after progression, complicating efforts to demonstrate an overall survival benefit.

Genmab and AbbVie’s collaboration on epcoritamab dates back to a 2020 deal, under which AbbVie paid $750 upfront to co-develop and commercialize a portfolio of Genmab’s bispecific antibodies. And both partners are already indicating that they will not treat this readout as the end of the story. They said they will engage regulators on next steps, and that follow-up data will be presented at an upcoming medical meeting, but neither said which one. They have also pointed to the trial’s timing, which started in early 2021, and said they plan to examine factors such as the pandemic period and the availability of newer anti-lymphoma agents that could have influenced outcomes.

The next developments to look out for are the two other phase 3 DLBCL studies expected to generate data in 2026, both testing epcoritamab in combination regimens, including a first-line program with standard chemotherapy and another combining epcoritamab with lenalidomide, an immunomodulatory drug that boosts immune activity and has shown clinical activity in B-cell lymphomas.