Englumafusp alfa plus glofitamab in B cell non-Hodgkin lymphoma: a phase 1 trial.

There is an unmet need for effective, off-the-shelf therapies for relapsed or refractory aggressive B cell non-Hodgkin lymphoma (B-NHL). Part 2 of the current study was an open-label, nonrandomized, phase 1 study of escalating doses of the CD19-4-1BBL co-stimulatory molecule, englumafusp alfa, in combination with glofitamab in patients with relapsed or refractory B-NHL. Obinutuzumab pretreatment was administered 7 days before the first glofitamab dose. Glofitamab step-up dosing in cycle 1 was followed by 11 cycles of glofitamab plus englumafusp alfa. Englumafusp alfa was administered at escalating doses, with the initial dose on cycle 2 day 8 (C2D8) or cycle 1 day 10 (C1D10). Primary objectives were to establish the maximum tolerated dose, and safety and tolerability. A total of 134 patients were enrolled, including 109 with aggressive B-NHL and 25 with indolent B-NHL. The maximum tolerated dose of englumafusp alfa was not reached; one dose-limiting toxicity occurred (grade 5 Pneumocystis jirovecii pneumonia). Adverse events were reported in 98.5% of all patients, with grade 3/4 adverse events in 59.0%. Grade 5 adverse events occurred in ten patients. In the subgroup of C2D8 patients with aggressive B-NHL (n = 83), overall response and complete metabolic response rates were 68.7% and 56.6%, respectively; among those without previous exposure to chimeric antigen receptor T cell therapy (n = 41), the corresponding rates were 73.2% and 65.9%. Pharmacodynamic changes following englumafusp alfa administration supported its co-stimulatory mode of action. These data demonstrate that the addition of englumafusp alfa to glofitamab is associated with encouraging efficacy and robust pharmacodynamic modulation, as well as a safety profile consistent with glofitamab monotherapy, in patients with relapsed or refractory B-NHL. CTIS identifier: 2022-502616-37-00 ; ClinicalTrials.gov identifier: NCT04077723 .