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

Abstract

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.

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