Epcoritamab in relapsed or refractory follicular lymphoma after two or more prior therapies

Evidence before this study

We searched PubMed on March 21, 2024, using the search terms “follicular lymphoma”, “relapsed”, “refractory”, and “chemoimmunotherapy”, “CAR T”, “bispecific”, or “treatment”, filtered for “clinical trial” or “randomized controlled trial”, for articles published in any language between Jan 1, 2010, and Jan 1, 2020. Before initiation of this study, few treatment options for patients with relapsed or refractory follicular lymphoma were available. Chemoimmunotherapy regimens like R-CHOP, R-bendamustine, and R-CVP were used; however, patients could become refractory to these therapies, and chemotherapy was associated with serious toxicities. Patients with relapsed or refractory follicular lymphoma in the MAGNIFY phase 3 trial (n=117; ) were treated with rituximab and lenalidomide; 67% of evaluable patients had a response, with 36% reaching complete response. Response rates among patients with double refractory disease or early relapse were lower. 1-year progression-free survival with lenalidomide and rituximab was 66%. Emerging therapeutic modalities aimed at addressing the unmet need for patients who are resistant to rituximab or chemotherapy included T-cell-engaging therapies such as chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engagers. At the time of EPCORE NHL-1 study initiation, CAR T therapies (axicabtagene ciloleucel [] and tisagenlecleucel []) and CD3 × CD20 bispecific antibodies (odronextamab [], mosunetuzumab [], and glofitamab []) were being evaluated for the treatment of relapsed or refractory follicular lymphoma. Compared with CAR T therapies, bispecific antibodies offer off-the-shelf convenience and might be more easily accessible. Epcoritamab, a CD3 × CD20 bispecific antibody, showed specific, highly potent antitumour activity in preclinical studies, inducing T-cell-mediated cytotoxicity against malignant CD20⁺ B cells. Subcutaneous administration was found to be effective while lowering concentrations of plasma cytokines compared with intravenous administration. Based on these studies and the unmet need for safe, effective, and convenient treatments, the first-in-human study EPCORE NHL-1 was initiated.

Added value of this study

Results from the phase 2, pivotal cohort coupled with the cycle 1 optimisation cohort of the EPCORE NHL-1 trial provide evidence of the safety and activity of epcoritamab in the relapsed or refractory follicular lymphoma setting. Epcoritamab monotherapy led to deep, durable responses in a heavily pretreated population, including in patients with high-risk disease features or those in later lines of treatment. A large analysis of measurable residual disease (MRD) showed high rates of MRD negativity, which was associated with improved progression-free survival. The safety profile was consistent with previous reports of epcoritamab. In the optimisation cohort for relapsed or refractory follicular lymphoma, the optimised, three-stage step-up dosing regimen and simple measures of prophylactic dexamethasone and hydration yielded lower rates of cytokine release syndrome, with no immune effector cell-associated neurotoxicity syndrome reported, and preliminary response rates suggesting no loss of activity.

Implications of all the available evidence

Epcoritamab demonstrated clinically meaningful activity with manageable safety in patients with relapsed or refractory follicular lymphoma after at least two previous lines of systemic therapy. The optimal strategy for treatment duration, whether fixed dosing or treatment to progression, is not yet determined. As a novel subcutaneous therapy with a treatment-to-progression dosing strategy, epcoritamab is a potential alternative to current treatment options in this setting.

Source: The Lancet Haematology