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 .

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Journal
Nature Medicine
Published
2026-07-16
DOI
https://doi.org/10.1038/s41591-026-04533-0
Primary Topic
CAR-T cell therapy research
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article
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0.00

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article

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

Candice Jamois, Giuseppe Gritti, Georgios Kazantzidis, Harriet S. Walter et al.
Nature Medicine
CAR-T cell therapy research
article

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

Candice Jamois, Giuseppe Gritti, Georgios Kazantzidis, Harriet S. Walter, Natalie Dimier, Roch Houot, Guillaume Cartron, Isabel Prieto González-Albo, Sabine Wilson, Carmelo Carlo‐Stella, Marie-Hélène Wasmer, Koorosh Korfi, Franck Morschhauser, Francesc Bosch, Martin Hutchings, N R Bartlett, Hervé Ghesquières, Michael John Dickinson, Jeremy Gallien, Abiraj Keelara, Heather Hinton, Sylvia Herter, Fritz Offner, William Townsend, Katharina Lechner
article en

Abstract

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 .

Nature Medicine
Roche (Switzerland) (CH), University of Copenhagen (DK), Humanitas University (IT), University College London Hospitals NHS Foundation Trust (GB), Washington University in St. Louis (US), Peter MacCallum Cancer Centre (AU), University Hospitals of Leicester NHS Trust (GB), Copenhagen University Hospital (DK), Rigshospitalet (DK), Centre Hospitalier Universitaire de Lille (FR), Centre Hospitalier Universitaire de Montpellier (FR), Roche Pharma AG (Germany) (DE), Hospices Civils de Lyon (FR), Ospedale Papa Giovanni XXIII (IT), Roche (United Kingdom) (GB), Universitair Ziekenhuis Brussel (BE), Vall d'Hebron Hospital Universitari (ES), Centre Hospitalier Universitaire de Rennes (FR), IRCCS Humanitas Research Hospital (IT), University College London (GB)
Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, Roche, Gilead Sciences, Celgene, F. Hoffmann-La Roche, BeiGene, Incyte, Roche Innovation Center Zurich, Seagen, Cancer Research UK, National Institute for Health and Care Research, University of Leicester, Swedish Orphan Biovitrum, Ipsen, Genentech, Kite Pharma, Pharmacyclics, Imperial Experimental Cancer Medicine Centre, Daiichi Sankyo Europe
Openalex Percentile: Top 11%
CAR-T cell therapy research
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