BP43131, a Phase 1 Dose Escalation Study: CD19 Targeted CD28 Costimulatory Agonist (RO7443904) Combined with Glofitamab Shows Promising Efficacy in Patients with Relapsed/Refractory Aggressive B-NHL

Background: Glofitamab has demonstrated significant single agent efficacy in patients with refractory or relapsed B-cell Non-Hodgkin Lymphoma (r/r B-NHL) and is approved in the 3L setting in DLBCL (Dickinson M. et al, NEJM, 2022). The combination of glofitamab with RO7443904, a bispecific antibody that simultaneously targets CD19 on B cells and CD28 on T cells, has shown a strong synergy with glofitamab in preclinical models (Sam et al. Blood 2024). We present full dose escalation data of BP43131 (NCT05219513), a first-in-human trial evaluating safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of RO7443904 in combination with glofitamab in patients with r/r B-NHL after at least two prior therapies.

Methods: Patients received glofitamab step-up dosing (SUD) (2.5/10/30mg) in cycles 1/2 after a single obinutuzumab dose (1000mg) at least three days prior to the first glofitamab dose. Two different treatment schedules were explored: the first dose of RO7443904 was either administered during glofitamab SUD (C1D10) or after completion of SUD (C2D8). All patients received both agents the same day from C3D1 onwards in 21-day cycles. Both compounds were administered intravenously (IV) with a fixed treatment duration (maximum 12 cycles). Dose escalation was conducted using a mCRM EWOC design. Response rates were assessed using Lugano criteria (Cheson et al. J Clin Oncol 2014) and Cytokine Release Syndrome (CRS) events were assessed using ASTCT consensus criteria (Lee et al. Biol Blood Marrow Transplant 2019).

Results: As of February 15th 2024, 53 patients were enrolled and received at least one dose of obinutuzumab (n=52), glofitamab (n=50) or RO7443904 (n=47) including 19 follicular lymphoma (FL) and 33 aggressive NHL (aNHL) (17 diffuse large B-cell lymphoma, 7 transformed FL, 4 Mantle cell lymphoma (MCL), 3 Richter’s transformation and 2 other transformed indolent NHL). RO7443904 doses ranged from 0.15 to 28mg with a maximum tolerated dose level not reached. Patients had a median age of 65 (range 41-86), were 38% female, 74% white, 71% ECOG 0 and primarily stage IV disease (63%). Patients had a median of 2 prior treatment lines (range 2-7), 43% were primary refractory and 29% had prior CAR-T cell therapy.

The safety profile was manageable and no additive or new safety signals as a result of combining RO7443904 with glofitamab were identified. The most common adverse events (AE) were CRS (54%), anemia (27%), ALT increase (19%), COVID-19 (19%), diarrhea (19%) and thrombocytopenia (19%). Grade 5 events were reported in 4 (8%) patients, none of them deemed related to study treatment. No Dose Limiting Toxicities were identified.

CRS events were mostly grade 1 (36%) or 2 (19%). Grade 4 events were reported in two patients with MCL. CRS was mostly confined to the first two glofitamab doses (2.5mg/10mg) with no events occurring after RO7443904 administration.

The ORR and CRR were 64% and 39% for aNHL (n=33) and 90% and 90% for FL (n=19). From the aNHL CAR-T naïve patients (n=18) and CAR-T pretreated (n=15), 33% and 47% had a CMR respectively. Across histologies, from the 30 patients who achieved CMR, 26 (87%) did so at the first tumor assessment and 27 (90%) were still in CMR at the time of the data-cut.

RO7443904 serum PK data were available for 47 patients who received multiple IV infusions of doses ranging from 0.15 to 28 mg. Thirty-two (32) patients received RO7443904 subcutaneously on one occasion. Consistent with target mediated drug disposition, RO7443904 clearance decreases as doses increase.

Pharmacodynamically, RO7443904 in combination with glofitamab boosted and sustained T-cell proliferation and effector functions (Korfi et al, submitted to ASH 2024), aligned with the expected mode of action (MoA) of CD28 costimulators.

Conclusions: These are the first clinical trial data showing that delivering a CD28 agonist in combination with glofitamab has promising efficacy in r/r B-NHL which is even more pronounced in FL patients. Furthermore, we have demonstrated for the first time in humans the MoA of a CD28 costimulatory bispecific in combination with a T-cell engaging bispecific antibody. This MoA is similar to what is observed for second-generation CAR T-cell therapies in r/r B-NHL. Updated analyses with longer follow up will be presented at the conference.