Abstract
Background: Primary central nervous system lymphomas (PCNSL) is an aggressive subtype of diffuse large B-cell lymphoma with poor outcomes. Prognosis is especially poor for patients over age 60 years and with relapsed/refractory (R/R) disease. While the currently available therapies provide acceptable response rates in the R/R setting, they are not durable. Similar to PCNSL, the management of secondary CNSL (SCNSL) is challenging and usually involves high dose methotrexate-based (HD-MTX) chemotherapy with limited options for those who progress/relapse following HD-MTX based therapies.
Bruton's tyrosine kinase (BTK) is a central signaling nodule of the B-cell receptor signaling pathway and therefore a promising therapeutic target in CNSL. Ibrutinib, a first-in-class BTK inhibitor has established activity in both primary and secondary CNSL with response rates around 50-60%, but the median PFS is short (~4-5 months). Hence, novel combination approaches utilizing ibrutinib backbone are needed to provide durable remissions.
Epcoritamab is a subcutaneously administered IgG1-bispecific antibody (BsAb) that recognizes the B-cell antigen CD20 on malignant cells and the T-cell antigen CD3, thus facilitating T-cell mediated cytotoxicity of CD20-expressing malignant cells. PCNSLs are sensitive to CD20 targeting as previously demonstrated by increased response rates when adding the monoclonal anti-CD20 antibody rituximab to other therapies such as ibrutinib. Therefore, combining epcoritamab with ibrutinib might provide a novel therapeutic approach that would work synergistically to improve outcomes in patients with R/R CNSL.
We hypothesize that epcoritamab can be safely used in CNSL patients when combined with ibrutinib. Patients with R/R CNSL are at higher risk of clinical deterioration, particularly when treated with a BsAb that might increase inflammation and edema in the CNS resulting in worsening clinical and neurologic deficits. Ibrutinib has been shown to induce significant tumor reduction within 2-4 weeks of therapy. Hence, the treatment schema includes a 'priming’ phase for patients with a 2-week introduction course of ibrutinib to significantly reduce tumor size and reduce the risk of epcoritamab associated cytokine release syndrome as well as immune effector cell-associated neurotoxicity syndrome and to prevent rapid deterioration of neurologic function from the recurrent/refractory disease.
Study Design and Methods: EIFEL (NCT07082868) is a multicenter, single-arm, open-label, non-randomized phase 1b study. Eligible patients are 18 years or older with histologically confirmed R/R PCNSL and SCNSL after one prior line of systemic therapy. Patients must have adequate end-organ function. Patients who received external beam radiation therapy to the CNS within 21 days of the first dose of the study drug are excluded.
The study consists of a safety lead-in (Cohort A) of 6 patients with either R/R PCNSL or R/R SCNSL followed by dose expansions for R/R PCNSL (Cohort B1) and R/R SCNSL (Cohort B2) with 10 patients each. Ibrutinib will start at 560 mg daily as single agent for 2 weeks followed by combination therapy for 12 cycles (28-day cycle) with ibrutinib dosed at 560 mg daily and subcutaneous epcoritamab dosed at the FDA-approved dosing schedule for DLBCL. Single agent epcoritamab will then be continued until completion of cycle 26.
The primary objective is to determine the safety and tolerability of epcoritamab in combination with ibrutinib in CNSL patients. Secondary objectives include frequency and severity of adverse events, overall response rate and complete response rate following C6, duration of response, median PFS and PFS at 16 weeks, 24 weeks and 48 weeks, overall survival, and evaluating CSF pharmacokinetics of epcoritamab for PCNSL and SCNSL patients. Diagnostic tissue, peripheral blood and CSF samples from different timepoints are collected for planned exploratory analysis including evaluation of T-cell function, and ctDNA testing.
