Epcoritamab Wins EU Approval for Relapsed/Refractory Follicular Lymphoma

The European Commission has granted conditional marketing authorization to epcoritamab-bysp (Tepkinly) for the treatment of adult patients with relapsed or refractory follicular lymphoma following 2 or more prior lines of systemic therapy.¹

The decision was based on data from the phase 1/2 EPCORE NHL-1 trial (NCT03625037), which showed that at a median follow-up of 17.4 months (interquartile range, 9.1-20.9), epcoritamab (n = 128) elicited an overall response rate (ORR) of 82.0% (95% CI, 74.3%-88.3%), which included a complete response (CR) rate of 62.5% (95% CI, 53.5%-70.9%).² At a median follow-up of 16.2 months, the median duration of response (DOR) with the agent was 21.4 months (95% CI, 13.7-not reached [NR]), with a duration of CR that was also NR.¹

“Follicular lymphoma can be challenging to treat and today’s approval of Tepkinly for the treatment of relapsed/refractory follicular lymphoma after 2 or more lines of systemic therapy marks an important milestone for patients in the European Union who are in need of more options offering a balance of meaningful efficacy and favorable safety,” Jan van de Winkel, PhD, president and chief executive officer of Genmab, stated in a news release. “Alongside our partner AbbVie, we are committed to exploring the continued development of epcoritamab as a potential core therapy across B-cell malignancies.”

The phase 2 portion of the study enrolled patients with CD20-positive follicular lymphoma with histologically confirmed grade 1 to 3A disease who had previously received 2 or more lines of therapy, including an alkylating agent or lenalidomide (Revlimid) or an anti-CD20 monoclonal antibody.² Patients needed to be at least 18 years of age and have relapsed on or been refractory to their last line of therapy received. They also needed to have an ECOG performance status ranging from 0 to 2.

Patients could not have primary central nervous system (CNS) lymphoma or known CNS involvement by lymphoma, nor could they have clinically significant cardiovascular disease, ongoing active infection in need of systemic therapy at the time of enrollment or within 3 weeks before study treatment was initiated. Other exclusion criteria included having known human immunodeficiency virus infection, history or current autoimmune disease, prior exposure to a bispecific antibody targeting CD3 and CD20, or receipt of CAR T-cell therapy within 30 days prior to study treatment.

Subcutaneous epcoritamab was given once weekly for cycles 1 to 3, once every 2 weeks for cycles 4 to 9, and once every 4 weeks for cycles 10 and beyond. Treatment was given in 28-day cycles and continued until intolerable toxicity or progressive disease.

The pivotal cohort of patients received step-up dosing in cycle 1, which comprised a priming dose of 0.16 mg on day 1, a 0.80-mg intermediate dose on day 8, and 48-mg full doses subsequently. This approach was leveraged to mitigate the risk and severity of cytokine release syndrome (CRS). Prophylaxis treatment with prednisolone at 100 mg was given 30 minutes to 2 hours before each dose of epcoritamab, followed by 3 consecutive days of daily prednisolone given at the same dose following epcoritamab administration. The study also included a planned separate optimization cohort, which examined a total of 86 patients with recommended 3-step-up doses for CRS mitigation.¹

ORR by independent review committee and Lugano criteria served as the trial’s primary end point. In the pivotal cohort, secondary end points comprised CR rate, time to CR, DOR, duration of CR, progression-free survival, overall survival, time to next therapy, safety, laboratory values, and minimal residual disease negativity rate at the time of the data cutoff date. In the cycle 1 optimization cohort, secondary end points were grade 2 or higher CRS and any-grade CRS following the first 48-mg dose of epcoritamab, as well as toxicities, laboratory values, and more.

Data from the study were published in The Lancet Haematology and had a data cutoff date of April 21, 2023. A total of 128 patients comprised the pivotal cohort. The median patient age was 65 years (range, 55-72). Most patients were male (62%), had an ECOG performance status of 0 (55%), creatinine clearance of at least 60 mL/min to under 90 mL/min (42%), Ann Arbor stage IV disease (60%), stage 3 to 5 disease by Follicular Lymphoma International Prognostic Index criteria at inclusion (61%), and bulky disease up to 6 cm (74%).²

The median number of prior lines of therapy was 3, with a range of 2 to 4; 37% of patients received 2 prior lines of treatment. Moreover, 42% of patients experienced progression within 24 months of starting frontline chemoimmunotherapy and 52% experienced progression within 24 months of starting any frontline treatment. Most patients were double refractory (70%) and 54% had primary refractory disease. Seventy-nine percent of patients were refractory to a prior anti-CD20 therapy and 69% were refractory to a prior systemic treatment. Five percent of patients previously received CAR T-cell therapy.

In the optimization cohort, 40% of patients experienced grade 1 CRS and 9% experienced a grade 2 event.¹ No grade 3 or higher cases of CRS were reported. No patients in this cohort had immune effector cell–associated neurotoxicity syndrome (ICANS)

The toxicity profile of the agent in the pivotal cohort was comparable to what has previously been reported with single-agent epcoritamab in the pivotal EPCORE NHL-1 diffuse large B-cell lymphoma cohort. In the pooled safety population (n = 382), the most common toxicities to be experienced by 20% or more of patients who received the agent were CRS, injection site reactions, fatigue, viral infection, neutropenia, musculoskeletal pain, pyrexia, and diarrhea. The most common serious toxicity reported in 10% or more of patients was CRS (34%). Moreover, 3.7% of patients experienced a toxicity that proved fatal; 9 patients had pneumonia, 4 had a viral infection, and 1 patient had ICANS.

References

1. Tepkinly (epcoritamab) receives second European Commission approval for the treatment of adults with relapsed/refractory follicular lymphoma. News release. Genmab A/S. August 19, 2024. Accessed August 19, 2024. https://ir.genmab.com/news-releases/news-release-details/tepkinlyr-epcoritamab-receives-second-european-commission
2. Linton KM, Vitolo U, Jurczak W, et al. Lancet Haematol. 2024;11(8):e593-e605. doi:10.1016/S2352-3026(24)00166-2