Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study

Background: Patients with relapsed or refractory (R/R) B-cell non-Hodgkin's lymphoma (B-NHL) have limited treatment options.Epcoritamab is a novel, CD3xCD20 bispecific antibody that induces T-cell-mediated cytotoxic activity against CD20-positive (CD20+) malignant B cells. Methods:In this phase 1 first-in-human dose-escalation study (NCT03625037) of subcutaneous (SC) epcoritamab in patients with R/R CD20+ B-NHL, patients received priming and intermediate doses followed by escalating full doses (0•0128-60 mg) of SC epcoritamab administered in 28-day cycles.The primary objectives were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D).Safety, antitumor activity, and immune biomarkers were also assessed.Findings: Sixty-eight patients with relapsed, progressive, or refractory CD20+ mature B-NHL received escalating full doses (0•0128-60 mg) of SC epcoritamab.No dose-limiting toxicities were observed, and the MTD was not reached; the full dose of 48 mg was identified as the RP2D.Common adverse events (AEs) were pyrexia (69%), primarily associated with cytokine release syndrome (CRS; 59%; all grade 1-2), and injection site reactions (47%; all but one were grade 1).There were no grade ≥3 CRS events, or discontinuations due to treatment-related AEs or death.Overall response rates (ORR) in R/R diffuse large B-cell lymphoma patients were 68% with 46% achieving complete response (CR) at full doses of 12-60 mg.At 48 mg, the ORR was 88% with 38% CR.Patients with R/R follicular lymphoma had an ORR of 90% with 50% CR at full doses of 0.76-48 mg.Epcoritamab induced robust and sustained B-cell depletion, CD4+/CD8+ T-cell activation and expansion, with modest increases in cytokine levels.Interpretation: This study met its primary objectives and demonstrated the safety and antitumor activity of single-agent SC epcoritamab in patients with R/R B-NHL, which supports ongoing phase 2 and phase 3 evaluation of epcoritamab.