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

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.

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. 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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. 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