CD19-CD28 costimulatory bispecific antibody plus glofitamab in R/R B-NHL: a phase 1 dose-escalation study

RO7443904 (CD19-CD28) is a novel costimulatory bispecific antibody designed to enhance T-cell activation and anti-tumor activity when combined with the CD20xCD3 bispecific antibody glofitamab. We report primary results from a phase 1 dose-escalation trial (BP43131; NCT05219513) evaluating this combination in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL). In this study, 52 patients with heavily pre-treated B-NHL (aggressive, n = 33; indolent, n = 19) received obinutuzumab pretreatment to mitigate cytokine release syndrome, glofitamab step-up dosing (2.5/10/30 mg), and the addition of CD19-CD28 (initiated on cycle 1 day 10 or cycle 2 day 8), for up to 12 cycles. The primary objectives were safety, tolerability, and identification of the maximum tolerated dose, which was not reached. Key secondary and exploratory objectives included efficacy, pharmacokinetics, and pharmacodynamics. The most common adverse event (AE) was cytokine release syndrome (53.8%), which was predominantly low-grade and occurred primarily during glofitamab step-up (grade 1: 36.5%; grade 2: 19.2%; grade 4: 3.8%). Five fatal AEs (9.6%) were reported, all considered non-related to study treatment. The combination demonstrated substantial efficacy, with objective and complete response rates (ORR/CRR) of 63.6% and 42.4% for aggressive B-NHL, and 89.5% for both ORR and CRR in indolent B-NHL. Pharmacodynamic analyses confirmed CD19-CD28 enhanced and sustained T-cell proliferation and effector functions in peripheral blood. In conclusion, the combination of glofitamab with CD19-CD28 had a manageable safety profile and promising early efficacy in relapsed/refractory B-NHL, providing a strong clinical proof-of-concept for enhancing T-cell engager therapy with CD28 costimulation in B-NHL.