Genmab A/S and AbbVie Inc. have secured European Commission approval for Tepkinly, or epcoritamab, in combination with lenalidomide and rituximab for adults with relapsed or refractory follicular lymphoma. The decision moves the CD3 and CD20 bispecific antibody into second-line and later treatment, extending epcoritamab beyond its established European role as a monotherapy for patients who have received at least two previous systemic therapies.
Why does the Tepkinly approval change where bispecific antibodies enter follicular lymphoma care?
The most important aspect of the approval is not simply the addition of another medicine to the European follicular lymphoma market. It changes when clinicians can use a bispecific T-cell engaging antibody. Epcoritamab can now be introduced following the first relapse or failure of an earlier treatment rather than being reserved principally for patients who have moved through several lines of therapy.
That shift matters because follicular lymphoma is commonly managed as a chronic, recurring disease. Initial treatment can produce long remissions, but the duration of disease control often becomes shorter after successive relapses. Introducing a potent immunotherapy-based combination earlier may therefore create an opportunity to achieve a deeper remission before patients accumulate additional treatment resistance, organ impairment or immune dysfunction.
Tepkinly is also the first bispecific-based regimen approved in Europe for follicular lymphoma in the second-line setting. The regimen combines three complementary mechanisms. Epcoritamab connects CD3-positive T cells with CD20-positive B cells, rituximab targets CD20 through established antibody-mediated mechanisms, and lenalidomide stimulates immune activity involving T cells and natural killer cells. The biological logic is stronger than simply adding three active medicines because the components are intended to reinforce immune-mediated lymphoma killing through different pathways.
The approval nevertheless does not mean every patient with a first relapse will automatically receive the combination. Follicular lymphoma treatment remains highly individualised, with decisions shaped by the duration of the first remission, prior exposure to anti-CD20 antibodies and bendamustine, disease burden, symptoms, comorbidities and the possibility of transformation into a more aggressive lymphoma. Tepkinly adds a powerful option, but it also makes treatment sequencing more complicated.
How strong is the EPCORE FL-1 evidence behind a possible new second-line treatment standard?
The regulatory case is supported by EPCORE FL-1, a global, randomised Phase 3 trial involving 488 patients across academic and community centres in 30 countries. Participants who had received at least one previous chemoimmunotherapy regimen were assigned to fixed-duration epcoritamab with lenalidomide and rituximab or lenalidomide and rituximab alone.
The trial design provides a more credible basis for practice change than the single-arm studies that supported several earlier approvals of bispecific antibodies in heavily pretreated lymphoma. Lenalidomide and rituximab, commonly known as R2, is an accepted chemotherapy-free treatment in relapsed follicular lymphoma, making it a clinically relevant control rather than an artificially weak comparator. Response and progression endpoints were also assessed by an independent review committee, reducing some of the bias associated with an open-label study.
The combination reduced the risk of disease progression or death by approximately 79% compared with R2 alone. At 16 months, an estimated 85.5% of patients receiving epcoritamab with R2 remained free from progression, compared with 40.2% in the control group. Median progression-free survival had not been reached with the Tepkinly combination at the primary analysis, while it was approximately 12 months with R2.
These results suggest that the benefit was not confined to producing additional partial responses. The combination generated deeper responses and substantially delayed disease progression, which is particularly relevant in an incurable lymphoma where the practical objective is to lengthen remission while preserving future treatment options.
The evidence still has limits. EPCORE FL-1 was open label, and the primary report was based on an interim analysis after 78% of the planned progression-free survival events had occurred. Median follow-up was 14.8 months, which is relatively short for an indolent lymphoma in which treatment benefits and late toxicities may unfold over several years. Overall survival was immature and did not cross the stringent prespecified threshold for formal statistical significance.
Why does the progression-free survival advantage matter more than the response headline?
High response rates are common in follicular lymphoma, especially when multiple active agents are combined. The more commercially and clinically significant question is whether those responses remain durable enough to delay further treatment. EPCORE FL-1 addressed that concern by showing a wide separation in progression-free survival rather than relying only on the proportion of patients whose tumours initially shrank.
The trial also reported a substantial improvement in the time before patients required another lymphoma therapy. At 16 months, approximately 92.8% of patients in the epcoritamab group had not started a subsequent treatment, compared with 64.9% in the R2 group. That difference could translate into longer treatment-free intervals, reduced exposure to additional therapies and greater preservation of later-line options.
Fixed-duration treatment strengthens that argument. Epcoritamab was administered for a maximum of 12 cycles rather than continued indefinitely until progression. Lenalidomide was also given through 12 cycles, while rituximab was concentrated within the first five cycles. A defined treatment endpoint may be attractive to clinicians, payers and patients when compared with therapies requiring continuous administration.
Durability beyond the current observation period remains the crucial unresolved issue. The combination could deliver a long remission after treatment stops, or progression curves could move closer together as follow-up matures. Longer observation is also needed to determine whether earlier disease control ultimately improves overall survival or mainly postpones the next therapy.
Can the safety and operational burden limit adoption despite a chemotherapy-free treatment label?
Describing the regimen as chemotherapy-free should not be interpreted as describing it as low intensity. Grade 3 or higher adverse events occurred in about 90% of patients receiving epcoritamab with R2, compared with 68% of those receiving R2 alone. Serious adverse reactions were reported in 44% of patients receiving the triplet.
Neutropenia, infections, rash, thrombocytopenia and anaemia were prominent concerns. Any-grade infections affected 77% of patients in the combination arm in the published analysis, while grade 3 or grade 4 infections occurred in approximately one-third. Treatment-emergent adverse events led to discontinuation of one or more study medicines in 19% of patients receiving the epcoritamab regimen, compared with 12% in the control group.
Cytokine release syndrome remains the most recognisable bispecific antibody risk. Most cases in EPCORE FL-1 were grade 1 or grade 2 and resolved with established management. A three-step dose escalation schedule reduced the incidence compared with the earlier two-step approach, supporting the idea that epcoritamab can be administered in an outpatient setting at experienced centres.
Outpatient administration still requires infrastructure. Treatment sites need staff trained to recognise cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, access to supportive medicines such as tocilizumab, infection prophylaxis protocols and the ability to monitor patients closely during initial dosing. Hypogammaglobulinaemia, cytopenias and recurrent infections may also require longer-term laboratory and supportive care.
The regimen combines subcutaneous epcoritamab, oral lenalidomide and intravenous rituximab. It may avoid conventional cytotoxic chemotherapy, but the early schedule remains visit intensive, with frequent epcoritamab administration during the first three cycles. Uptake may therefore be faster at large lymphoma centres than at smaller facilities without established bispecific antibody programmes.
How will Tepkinly compete with other chemotherapy-free regimens and cellular therapies in Europe?
Tepkinly enters a treatment market that is becoming more competitive rather than replacing a single dominant standard. R2 remains widely recognised and has the advantage of longer clinical experience. Tafasitamab combined with lenalidomide and rituximab has also been authorised in Europe for relapsed or refractory follicular lymphoma after at least one previous systemic treatment, creating a direct contest between two antibody-based triplets built on the same R2 backbone.
The two regimens use different biological strategies. Tafasitamab is a CD19-directed monoclonal antibody, while epcoritamab is a CD3 and CD20 bispecific antibody that directly recruits T cells. No head-to-head trial has established that one triplet is clinically superior. Cross-trial comparisons are unreliable because patient characteristics, response definitions, follow-up periods and statistical plans differ.
Tepkinly’s subcutaneous administration and strong progression-free survival result may support adoption. Tafasitamab, however, does not carry the same cytokine release syndrome management burden associated with T-cell engagement. Clinicians and health technology assessment bodies will therefore examine the complete package, including efficacy durability, infection risk, infusion or injection schedules, supportive care requirements and total treatment cost.
Bispecific antibodies also compete indirectly with chimeric antigen receptor T-cell therapies in later-line follicular lymphoma. Epcoritamab offers an off-the-shelf treatment without cell collection, personalised manufacturing or the logistical delays associated with cellular therapy. It is not yet clear whether earlier bispecific use will reduce later demand for CAR T-cell treatment, alter its effectiveness or complicate sequencing through T-cell exhaustion and antigen-related resistance.
What will determine whether the approval becomes a commercial turning point for Genmab and AbbVie?
The European decision strengthens epcoritamab as a franchise rather than a medicine restricted to one late-line indication. Genmab A/S and AbbVie Inc. are developing the antibody across B-cell malignancies, treatment combinations and earlier disease stages. Demonstrating superiority in a randomised Phase 3 trial supports the broader strategy of using epcoritamab as a combination backbone rather than relying only on monotherapy in heavily pretreated patients.
AbbVie Inc. is responsible for commercialisation across most markets outside the shared United States and Japanese arrangements. The European approval therefore expands the addressable population, but revenue growth will depend on national reimbursement decisions rather than the European Commission authorisation alone. Pricing negotiations and health technology assessments can produce substantial differences in launch timing and access between European countries.
Payers will examine whether the progression-free survival gain justifies the cost of adding a bispecific antibody to lenalidomide and rituximab. They may also evaluate hospital resource use, infection-related admissions, monitoring costs and dose interruptions. A regimen that prevents progression but requires intensive early management may produce a different economic result from one that is less effective but operationally simpler.
The approval also increases the importance of the ongoing first-line EPCORE FL-2 programme, which is comparing epcoritamab with R2 against chemoimmunotherapy in previously untreated follicular lymphoma. Success in that setting would move the bispecific strategy from relapse management into initial therapy, creating a much larger commercial opportunity. Failure, excess toxicity or insufficient durability would reinforce the view that the regimen is better suited to selected relapsed patients.
Which unanswered questions will shape real-world use of Tepkinly over the next two years?
Longer follow-up from EPCORE FL-1 will be central. Clinicians will want to see whether progression-free survival remains strongly separated after treatment completion, whether an overall survival advantage emerges and whether prolonged B-cell depletion produces delayed infections or immunoglobulin-related complications.
Subgroup performance will also matter. Patients whose disease progresses within 24 months of initial therapy generally have a less favourable prognosis and may require more aggressive treatment. Prior bendamustine exposure is another important variable because recent bendamustine treatment can impair T-cell fitness, potentially affecting the performance of a T-cell engaging antibody. The published trial contained too few patients with recent bendamustine exposure to draw firm conclusions.
Real-world evidence will show whether community centres can reproduce the trial’s cytokine release syndrome management, infection prophylaxis and dose intensity. It will also clarify which patients can complete all 12 cycles, how frequently lenalidomide requires dose reduction and whether older or medically complex patients experience the same benefit-risk balance seen in the broader trial population.
The European approval gives Tepkinly a credible opportunity to become an important second-line follicular lymphoma option. Its progression-free survival result is difficult to dismiss, and the fixed-duration design differentiates the regimen from continuously administered therapies. The decisive test now moves beyond regulatory efficacy into reimbursement, treatment sequencing, long-term safety and routine clinical execution.
