RG6333 / Roche - LARVOL DELTA

Distinct mechanisms of CD28 and 4-1BB costimulation in glofitamab combination therapies for relapsed/refractory non-Hodgkin lymphoma (R/R NHL) (AACR 2025) - P1, P1/2 | "While both costimulators are designed to enhance the anti-tumor effects of T-cell engagers, we present, for the first time, key differences in the mechanisms and response profiles of CD28 and 4-1BB costimulation in these combinations. Exploratory biomarker analyses included 28 indolent and aggressive NHL patients treated with RO7443904 (CD19-CD28) and 99 with englumafusp alfa (CD19-4-1BBL) on Cycle 2 (C2) Day 8, after completion of glofitamab step-up dosing, followed by administration on the same day as glofitamab from C3 onwards (Q3W) for a fixed duration of 12 cycles. Our findings reveal distinct mechanisms of CD28 and 4-1BB costimulation with glofitamab, which may explain their different response dynamics. Specifically, 4-1BB promotes a sustained and prolonged immune response, while CD28 triggers rapid T-cell activation and proliferation. Moreover, 4-1BB appears to bypass macrophage suppression, and benefits from cDC-mediated antigen presentation and CD8..."

Combination therapy • IO biomarker • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • B2M • CD28 • CD4 • CD8 • CREBBP • PD-1 • TP53

CD19-CD28 (RO7443904) Combination with Glofitamab Enhances T-Cell Proliferation and Effector Function in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma (R/R NHL) (ASH 2024) - P1, P1/2 | "This enhanced response appears to benefit patients with a less immunosuppressive tumor microenvironment and more active T-cell infiltration. Overall, our PD and biomarker findings support the rationale for this combination as an effective off-the-shelf therapy for patients with R/R NHL."

Clinical • IO biomarker • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD28 • CD4 • CD8 • CREBBP • KMT2D • PD-1 • TP53

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 (ASH 2024) - P1 | "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. 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."

Clinical • P1 data • Anemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Infectious Disease • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Novel Coronavirus Disease • Oncology • Richter's Syndrome • Thrombocytopenia

BP43131: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of RO7443904 in Combination With Glofitamab in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma (clinicaltrials.gov) - P1 | N=53 | Terminated | Sponsor: Hoffmann-La Roche | N=200 ➔ 53 | Trial completion date: Apr 2025 ➔ Jul 2024 | Recruiting ➔ Terminated | Trial primary completion date: Apr 2025 ➔ Jul 2024; The study was terminated due to sponsor portfolio re-alignment.

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD20

CD19-CD28: An affinity-optimized CD28 agonist for combination with glofitamab (CD20-TCB) as off-the-shelf immunotherapy. (PubMed, Blood) - "We developed a bispecific CD19-targeted CD28 agonist (RG6333, CD19-CD28) to enhance the efficacy of glofitamab and similar TCBs by delivering signal 2 to tumor-infiltrating T cells. CD19-CD28 distinguishes itself from the superagonistic antibody TGN1412, as its activity requires the simultaneous presence of a TCR signal and CD19 target binding...Our findings highlight CD19-CD28 as a safe and highly efficacious off-the-shelf combination partner for glofitamab, similar TCBs, and other costimulatory agonists. CD19-CD28 is currently in a Phase 1 clinical trial in combination with glofitamab."

IO biomarker • Journal • Hematological Malignancies • Lymphoma • Oncology • CD20

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of RO7443904 in Combination With Glofitamab in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma (clinicaltrials.gov) - P1 | N=200 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Apr 2024 ➔ Apr 2025 | Trial primary completion date: Apr 2024 ➔ Apr 2025

Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD20

RG6333 (CD19-CD28), a CD19-Targeted Affinity-Optimized CD28 Bispecific Antibody, Enhances and Prolongs the Anti-Tumor Activity of Glofitamab (CD20-TCB) in Preclinical Models (ASH 2022) - P1 | "In contrast, TGN1412, a CD28 superagonist antibody, induced strong T cell activation, proliferation and cytokine secretion in vitro and in huNSG. Scheduling studies with glofitamab and RG6333 in huNSG suggest a safe and potent treatment regimen by using Gazyva pre-treatment followed by a staggered infusion of glofitmab and RG6333 applying an interval of three days at the first treatment cycle...Interestingly, the alternation of RG6333 with an alternative 4-1BB costimulatory agent (RG6076; CD19-4-1BBL) completely prevented tumor relapse during glofitamab treatment for more than 120 days when RG6333 was given for the first treatment cycles followed by RG6076 at later cycles...Optimal scheduling including alternation of costimulatory bispecific antibodies suggest a powerful off-the-shelf T cell redirection approach as an alternative to CAR-T cell therapies. RG6333 is currently in a phase I, open-label, dose-escalation study in combination with glofitamab (NCT05219513)."

Preclinical • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20 • CD4 • CD8

Phase 1 Study of CD19 Targeted CD28 Costimulatory Agonist in Combination with Glofitamab to Enhance T Cell Effector Function in Relapsed/Refractory B Cell Lymphoma (ASH 2022) - P1 | "Across the different study parts, the treatment schedule is consistent with a single fixed dose of obinutuzumab (1000mg intravenously) given at least 3 days prior to glofitamab step up dosing (2.5/10/30mg)...Commencement of part 4, the expansion phase, including decision on the RO7443904 dose will be guided by a concerted review of safety, PK, and PD data from all dose escalation parts...Figure 1: Efficacy study in a disseminated DLBCL model in humanized NSG mice treated with monotherapy of glofitmab (0.15 mg/kg) or CD19-CD28 (1 mg/kg) as well as with a combination of both. The data suggest a strong anti-tumor effect when both agents are combined."

Combination therapy • P1 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immune Modulation • Indolent Lymphoma • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19