On July 6, 2026, the European Commission approved TEPKINLY (epcoritamab) in combination with lenalidomide and rituximab for adults with relapsed or refractory follicular lymphoma after at least one prior systemic therapy. The decision appears to extend a regulatory trend that was already underway. The same regimen received FDA approval in November 2025, while epcoritamab monotherapy had previously been approved in both the United States and Europe for heavily pretreated patients.
The approval introduces the first bispecific-based regimen authorized in Europe for follicular lymphoma at first relapse. The importance of the approval also lies in the broader adoption of this treatment approach across major regulatory jurisdictions. With both the FDA and European Commission now endorsing epcoritamab-R² in this setting, the clinical implications of EPCORE FL-1 become increasingly relevant to routine practice. Should epcoritamab-R² become the preferred standard at first relapse, and, if so, what role remains for later-line bispecific therapy and CAR-T?
The Road to EPCORE FL-1
CAR-T cell therapies first demonstrated that deep and durable remissions could be achieved in patients with relapsed FL after multiple prior treatments. Shortly thereafter, bispecific antibodies introduced a new off-the-shelf approach capable of redirecting endogenous T cells against CD20-positive lymphoma cells without the manufacturing requirements of cellular therapy.
Mosunetuzumab established the clinical potential of CD20×CD3 bispecific antibodies in relapsed or refractory follicular lymphoma, followed by epcoritamab monotherapy for patients who had received at least two prior systemic therapies. These approvals were important, but they were largely positioned in later treatment lines and were primarily supported by single-arm studies.
EPCORE FL-1 was designed to answer a different question. Rather than asking whether a bispecific antibody could rescue heavily pretreated disease, investigators asked whether adding epcoritamab to rituximab and lenalidomide could improve outcomes in patients who relapsed after frontline therapy.
The answer appears to be yes.
EPCORE FL-1 Changed the Conversation
EPCORE FL-1 was a global, open-label, randomized phase III study that enrolled 488 patients with relapsed or refractory follicular lymphoma after at least one prior line of therapy. Patients were assigned to receive subcutaneous epcoritamab-R² (n=243) or R² alone (n=245). Epcoritamab was administered in 28-day cycles for up to 12 cycles, making the triplet a fixed-duration treatment.
The trial met both primary endpoints: epcoritamab-R² reduced the risk of disease progression or death by 79% compared with R² alone (HR 0.21), and the overall response rate was 96% with the triplet vs 81%. Additionally, complete responses were achieved in 74% of patients compared with 43%, respectively.
These results are particularly relevant because they were generated in a randomized phase III comparison against R², an established chemotherapy-free treatment, rather than against a historical control or an inactive comparator.
The magnitude of benefit must nevertheless be considered alongside the additional treatment burden. The safety profile was described as consistent with the known profiles of the individual components, but serious adverse reactions occurred in 44% of patients receiving epcoritamab-R². Common adverse reactions included neutropenia, infections, rash, fatigue, cytopenias, cytokine release syndrome, hypogammaglobulinemia, injection-site reactions, and pneumonia.
From Clinical Trial to Clinical Practice
FL accounts for a larger proportion of non-Hodgkin lymphomas in European populations (11-29%) than in non-European populations (2-18%). FL is generally considered incurable, and no standard-of-care treatment exists for patients with third-line or later disease. Even among patients who achieve remission, relapse remains common.
The magnitude of benefit observed in the trial makes epcoritamab-R² a compelling candidate for a new second-line benchmark. The regimen is chemotherapy-free, fixed in duration, and supported by randomized evidence.
Despite its impressive efficacy, EPCORE FL-1 leaves several questions unanswered. Overall survival data remain immature, and longer follow-up is needed to determine the durability of benefit. Follicular lymphoma is a biologically diverse disease, it is also unclear whether all patients at first relapse require a bispecific-containing triplet.
Disease burden, pace of relapse, patient fitness, infection risk, prior exposure to lenalidomide, and treatment goals will continue to influence decision-making. For some patients, less intensive approaches may remain appropriate.
At the same time, earlier use of a bispecific antibody inevitably raises questions about sequencing.
What Happens to Mosunetuzumab?
The success of EPCORE FL-1 does not diminish the value of mosunetuzumab, but it may alter where the therapy is used.
Mosunetuzumab remains an important fixed-duration option for patients with relapsed or refractory disease and offers the convenience of single-agent treatment. However, if epcoritamab-R² becomes widely adopted after first relapse, the available space for later-line CD20×CD3 bispecific therapy may narrow.
An unanswered question is whether patients who have already received one CD20×CD3 bispecific antibody will derive equivalent benefit from another. Clinical experience in this setting remains limited, making future sequencing studies increasingly important.
As a result, the role of mosunetuzumab may evolve from pioneering the bispecific era to serving as a later-line strategy for older or frailer patients for whom lenalidomide-associated cytopenias, thrombosis risk, rash, or cumulative triplet toxicity are concerns. Mosunetuzumab could remain an important third-line option where epcoritamab-R² was not used at first relapse because of access, contraindications, physician preference, or patient choice.
Does Earlier Epcoritamab Change the Role of CAR-T?
The impact on CAR-T therapy may be even more important. It remains one of the most effective treatment approaches available for relapsed follicular lymphoma and offers the possibility of prolonged treatment-free remission after a single infusion. Its mechanism is distinct from that of CD20-directed bispecific antibodies, and its role is unlikely to disappear because of EPCORE FL-1.
Instead, the approval may shift CAR-T toward a more selective position within the treatment pathway. Patients with high-risk disease biology, early progression, or relapse following bispecific-based treatment may increasingly become the population most likely to benefit from cellular therapy. In this scenario, epcoritamab-R² would not replace CAR-T but would redefine when CAR-T is used.
Future studies will need to determine how prior exposure to T-cell-engaging therapies influences subsequent CAR-T outcomes and whether earlier bispecific treatment affects long-term therapeutic sequencing.
A New Benchmark, Not the Final Answer
The European Commission approval expands the reach of EPCORE FL-1 and signals growing confidence in moving bispecific therapy earlier in the disease course. By expanding access to a treatment strategy that had already received FDA approval, the decision helps globalize a new therapeutic paradigm in follicular lymphoma.
Europe has now embraced the EPCORE FL-1 strategy. More broadly, the challenge ahead is determining how best to integrate it with mosunetuzumab, CAR-T therapy, and the growing number of immune-based approaches entering clinical practice.
Whether epcoritamab-R² ultimately becomes the preferred treatment at first relapse will depend on long-term follow-up, real-world experience, access, reimbursement, and physician adoption. However, the central contribution of EPCORE FL-1 is already clear.
Follicular Lymphoma (FL): Evolving Biology and Modern Therapeutic Paradigms