Multinational phase 1 trial of englumasfusp alfa plus glofitamab in B-cell non-Hodgkin lymphoma

There is an unmet need for off-the-shelf therapies for relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (R/R B-NHL). A multinational phase 1 trial evaluated escalating doses of the CD19-4-1BLL co-stimulatory molecule englumafusp alfa in combination with the bispecific anti-CD20/anti-CD3 monoclonal antibody glofitamab in patients with R/R B-NHL. Obinutuzumab pretreatment was administerd 7 days before the first glofitamab dose. Glofitamab step-up dosing in cycle 1 was followed by 11 cycles of glofitamab plus englumafusp alfa. The initial dose of englumafusp alfa was administered on cycle 2 day 8 (C2D8) or C1D10. Primary objectives were to establish the maximum tolerated dose (MTD), and safety and tolerability. A total of 134 patients were enrolled, including 109 with aggressive B-NHL and 25 with indolent B-NHL. The MTD of englumafusp alfa was not reached; one dose-limiting toxicity occurred (grade 5 pneumonia). Adverse events were reported in 98.5% of patients, with grade 3-4 AEs in 59.0% and grade 5 AEs in 13%. 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 CAR T cell therapy (n=43), the corresponding rates were 73.2% and 65.9%. The median progression-free survival and overall survival for aggressive B-NHL in the C2D8 cohort were 9.7 months (95% CI 4.9-25.1) and 24.1 months (12.6-NE), respectively. Pharmacodynamic changes following englumafusp alfa administration supported its co-stimulatory mode of action. The authors conclude that these data demonstrate that the addition of englumafusp alfa to glofitamab is associated with encouraging efficacy and a safety profile consistent with glofitamab monotherapy in patients with R/R B-NHL.