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990 Englumafusp Alfa (CD19-4-1BBL) Combined with Glofitamab Is Safe and Efficacious in Patients with r/r B-NHL: Extended Follow up Analysis of the Dose-Escalation Part of Phase 1 Trial BP41072

Program: Oral and Poster Abstracts
Type: Oral
Session: 627. Aggressive Lymphomas: Pharmacologic Therapies: Chemotherapy-free Combinations for Relapsed Aggressive Lymphomas
Hematology Disease Topics & Pathways:
Research, Clinical trials, Combination therapy, Lymphomas, Non-Hodgkin lymphoma, Drug development, Bispecific Antibody Therapy, Clinical Research, Diseases, Aggressive lymphoma, Treatment Considerations, Biological therapies, Lymphoid Malignancies, Study Population, Human
Monday, December 9, 2024: 5:45 PM

Martin Hutchings, MD, PhD1, Michael J. Dickinson, MBBS, DMedSci2, Giuseppe Gritti, MD, PhD3*, Carmelo Carlo-Stella, MD4, William Townsend5*, Francesc Bosch, MD, PhD6,7, Nancy L. Bartlett, MD8, Guillaume Cartron9*, Herve Ghesquieres, MD, PhD10*, Roch Houot, MD, PhD11*, Harriet S. Walter, MD, PhD, MRCP12*, Fritz Offner, MD, PhD13, Natalie Dimier, PhD14*, Candice Jamois, PharmD15*, Lance Smith16*, Sylvia Herter, PhD17*, Denis Sahin, PhD18*, Abiraj Keelara, PhD19*, Koorosh Korfi, PhD20, Jeremy Gallien19*, Marie-Helene Wasmer15*, Heather Hinton21*, Matt Whayman16*, Isabel Prieto22*, Georgios Kazantzidis15*, Katharina Lechner23* and Franck Morschhauser, MD, PhD24

1Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
2Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
3Department of Oncology-Hematology, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
4IRCCS Humanitas Research Hospital, Humanitas University, ROZZANO, ITA
5NIHR Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, United Kingdom
6Hematology Department, Hospital Universitario Vall d’Hebron, Barcelona, Spain
7Hematology Department, Vall d’Hebron Institute of Oncology (VHIO), University Hospital Vall d’Hebron, Barcelona, Spain
8Division of Oncology, Washington University School of Medicine, St. Louis, MO
9CHU Montpellier, Montpellier, FRA
10Department of Hematology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France
11CHU Rennes, Univ Rennes, Inserm & EFS, Rennes, France
12University of Leicester and University Hospitals Leicester, Leicester, GBR
13Universitair Ziekenhuis Ghent, Ghent, Belgium
14Roche Innovation Center Welwyn, Roche, Welwyn, GBR
15Pharma Research and Early Development, Roche Innovation Center Basel, Roche, Basel, Switzerland
16Innovation Center Welwyn, Roche, Welwyn, United Kingdom
17Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland
18Product Development Oncology and Hematology, Roche Innovation Center Basel, Roche, Basel, Switzerland
19Roche Innovation Center, Basel, Switzerland
20Roche Innovation Center Zurich, Roche, Schlieren, -- Select, Switzerland
21Product Development, Innovation Center Basel, Roche, Basel, Switzerland
22Product Development, Innovation Center Welwyn, Roche, Welwyn, United Kingdom
23Pharma Research and Early Development, Innovation Center Munich, Roche, Penzberg, Germany
24Centre Hospitalier Régional Universitaire de Lille, Lille, France

Background

Englumafusp Alfa is a co-stimulatory antibody-like fusion protein targeting CD19 on B cells and 4-1BB on immune cells. Glofitamab single-agent has demonstrated efficacy in patients (pts) with relapsed/refractory B-cell Non-Hodgkin Lymphoma (r/r B-NHL) and is approved after at least two prior treatment lines. Preclinical in vivo models have confirmed that administering englumafusp Alfa in combination with glofitamab enhances, prolongs, and deepens anti-tumor activity (C. Claus et al., 2019). We present PFS, OS, DoR and extended follow-up data of the final dose escalation of BP41072 (NCT04077723), a phase 1b study combining englumafusp alfa with glofitamab in pts with r/r B-NHL.

Methods

Pts with r/r B-NHL after at least one prior treatment, ECOG 0-1, received glofitamab step up dosing (2.5/10/30mg) after a single obinutuzumab dose (1000mg). One week after (i.e. cycle 2 day 8), pts received englumafusp alfa and from C3D1 onwards both agents were given the same day Q3W. Therapy was administered intravenously for a maximum of 12 cycles. Dose escalation was conducted using a mCRM EWOC model. Complete response rates (CRR) and best overall response rates (BORR) were assessed using Lugano criteria.

Results

As of the Clinical cut-off date on June 3, 2024, 134 pts were enrolled. Among them, 83 pts had aggressive NHL (aNHL), including 44 DLBCL, 16 HGBL-DH/TH, 18 trFL, 3 transformed other indolent NHL and 2 FL grade 3B. Additionally, 24 pts had indolent disease (iNHL), comprising 23 FL and 1 MZL. Englumafusp alfa doses ranged from 0.36 up to 75mg without reaching a maximum tolerated dose level. Pts (aNHL/iNHL) had median age 63/64, 41%/42% were female, 98%/88% were white, 65%/79% were not Hispanic or Latino, 14%/0 were Hispanic or Latino, 47%/29% presented with ECOG 1, and 52%/54% had stage IV disease. Both patient groups had a median of 3 prior treatment lines (range 1-8/6), 19%/8% were primary refractory, and 49%/4% had received prior CAR-T cell therapy. Patients received a median of 8.5 treatment cycles (1-12).

Across the 134 safety-evaluable pts (all histologies), the most common adverse events were cytokine release syndrome (CRS, 55.2%), anemia (32.1%), COVID-19 (29.9%), and neutropenia (27.6%). Grade 5 events were reported in 9 (6.7%) pts and were related to study treatments in 3 patients (pleurisy, organising pneumonia and pneumocystis jirovecci pneumonia). The latter event qualified as a dose-limiting toxicity (n=1).

CRS was mostly confined to the first two glofitamab doses, being related to only glofitamab in 69 pts (51.5%), related to both glofitamab and englumafusp alfa in 11 pts (8.2%) and to englumafusp alfa alone in 7 (5.2%) pts. CRS events were mostly grade 1 (48.5%), grade 2 events occurred in 19 (14.2%) pts and grade 3 in 1 (0.7%) pt. The overall and CRS safety profiles are comparable for subpopulations within the aNHL patients (n=83 pts). No additive or synergistic safety concerns were identified from the combination of englumafusp alfa with glofitamab.

Across all doses investigated, BORR (aNHL/iNHL) was 67.5%/ 91.7% with CRR of 56.6%/79.2%. The majority of responders (33/56 (58.9%) aNHL, 14/22 (63.6%) iNHL) were still in response at data cut. For all pts aNHL the median follow up duration was 16.2 months and the median duration of response (mDOR) was 31.5 months (95% CI: (13.8, NE)). The median progression-free survival (mPFS) and median overall survival (mOS), for aNHL pts were 9.7 months (95% CI: 4.9, 25.1), and 20.9 months (95%, CI 12.1, NE), respectively with a 1-year PFS rate of 45.6% . While the median PFS time for iNHL had not been reached at the time of the data cut-off, the PFS rate at 1 year was 82.6%. Circulating tumor DNA data in relation to clinical efficacy will also be presented at the meeting.

In a subgroup analysis CRR and BORR were higher in CART-naïve aNHL with 65.9% and 73.2% compared to pts after prior CAR-T therapy (47.6%, 61.9%). This was also reflected in a favorable mDoR of 31.5 months, mPFS of 15.7 months (95%, CI 5.4 , NE), 1-year PFS rate 50.9% and mOS of 32.9 months (95%, CI 12.6,NE) compared to the CART pretreated patient population (mDoR 13.8 months, mPFS 5.7 months, 1-year PFS rate 41%, mOS 13.4 months). Of note, updated data will be shared at the conference.

Conclusions

The off-the shelf glofitamab plus englumafusp alfa combination administered as a fixed duration treatment demonstrates a favorable activity in different r/r NHL subpopulations. A Phase 2 expansion study is currently underway.

Disclosures: Hutchings: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Incyte: Research Funding; Janssen/J&J: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Dickinson: Roche: Consultancy, Honoraria, Speakers Bureau; Adicet Bio: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Kite: Consultancy, Honoraria, Speakers Bureau. Gritti: Takeda, Abbvie, Roche, Kite-Gilead, Ideogen, Genmab: Membership on an entity's Board of Directors or advisory committees; Janssen, Beigene, Kite-Gilead, Roche, Sandoz: Other: Support for attending meetings; Ideogen, Takeda: Speakers Bureau. Carlo-Stella: ADC Therapeutics: Consultancy, Honoraria, Research Funding; Humanitas University, Milano (Italy): Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi, ADC Therapeutics: Consultancy; Sanofi, ADC Therapeutics, Celgene/Bristol-Myers Squibb, Karyopharm Therapeutics, Roche, Novartis, Scenic Biotech, Janssen Oncology, Merck Sharp & Dohme, SOBI, AbbVie, Genmab, AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca, Celgene/Bristol-Myers Squibb, Incyte, Janssen Oncology, Takeda, Novartis, ADC Therapeutics, Roche, Gilead, SOBI, Merck Sharp & Dohme: Honoraria; Gilead: Honoraria; Incyte: Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Scenic Biotech: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics, Roche, Sanofi: Research Funding; Takeda: Honoraria; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Townsend: Research funding paid to my institution (UCL) by Roche: Research Funding; Roche, Abbvie, Sobi, Kite, Takeda, Janssen: Honoraria; Roche, Abbvie, Takeda, Sobi: Membership on an entity's Board of Directors or advisory committees, Other: Travel to international conferences from Roche; Roche, Abbvie, Sobi, Kite, Takeda: Consultancy. Bosch: Lava Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Advantage Allogene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Enterome: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony. Bartlett: ADC Therapeutics: Research Funding; Washington University School of Medicine: Current Employment; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Kite Pharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Celegne: Research Funding; BMS: Research Funding; Autolus: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Foresight Diagnostics: Membership on an entity's Board of Directors or advisory committees. Cartron: MabQi, Onwards Therapeutics, Abbvie, Roche, BMS: Membership on an entity's Board of Directors or advisory committees; MedxCell, Onwards Therapeutics, MabQi, Emercell, Roche, BMS, Abbvie: Consultancy; Jansen, Gilead, Novartis, Roche, BMS Abbvie: Honoraria. Ghesquieres: Gilead, Roche, BMS, Abbvie, Takeda: Honoraria; Roche, BMS, Takeda: Consultancy. Houot: BMS/Celgene: Honoraria; Gilead Sciences: Consultancy, Honoraria; ADC Therapeutics: Honoraria; Janssen: Honoraria; Kite, a Gilead Company: Consultancy, Honoraria. Walter: NIHR/CRUK, Pfizer, Innovate UK: Honoraria, Research Funding. Dimier: Roche: Current Employment, Current equity holder in publicly-traded company. Jamois: Roche: Current Employment, Current equity holder in publicly-traded company. Smith: Roche: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Herter: Roche Glycart AG: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Sahin: Roche: Current Employment, Current equity holder in publicly-traded company. Keelara: Roche: Current Employment, Current holder of stock options in a privately-held company. Korfi: Roche: Current Employment, Current equity holder in publicly-traded company. Gallien: Roche: Current Employment. Wasmer: Roche: Current Employment, Current equity holder in publicly-traded company. Hinton: Roche: Current Employment, Current equity holder in publicly-traded company. Whayman: Roche: Current Employment, Current equity holder in publicly-traded company. Prieto: Roche: Current Employment, Current equity holder in publicly-traded company. Kazantzidis: Roche: Current Employment, Current equity holder in publicly-traded company. Lechner: Roche: Current Employment, Current equity holder in publicly-traded company. Morschhauser: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Other: Payment for Expert Testimony, Honoraria for Scientific Lectures; Chugai: Honoraria; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria; Epizyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy.

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