englumafusp alfa (RG6076) / Roche - LARVOL DELTA

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 (ASH 2024) - P1/2 | "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). 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."

Clinical • P1 data • Anemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Infectious Disease • Lymphoma • Marginal Zone Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pneumonia • Respiratory Diseases

Integrated Quantitative Clinical Pharmacology Analysis Identifies Optimal Englumafusp Alfa Dose Range for Proof-of-Concept Study with Glofitamab in Second-Line Large B-Cell Lymphoma Patients (ASH 2024) - P1/2 | "Two doses with distinct exposures, which maximize the number of patients with englumafusp alfa steady-state exposure (Cav,ss) within the in vivo efficacious dose range and optimal PD response range, were selected for further dose optimization in the next study phase. Conclusion : This study demonstrates the utility of integrating totality of evidence (safety, efficacy, PK, PK/PD, biomarkers and non-clinical) with quantitative in silico approaches to identify the optimal dose range of englumafusp alfa, a bispecific antibody with no single-agent activity, to maximize benefit/risk when combined with glofitamab."

Clinical • IO biomarker • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Large B Cell Lymphoma • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD8 • IL2RA • PD-1

Englumafusp Alfa (CD19-4-1BBL) and Glofitamab Combination in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma (R/R NHL): Biomarker Results from a Phase I Dose-Escalation Trial (ASH 2023) - P1/2 | "In this study, we demonstrated the MoA of englumafusp alfa in R/R NHL and key PD effects in combination versus glofitamab monotherapy that will support optimal biological dose finding. Furthermore, the observed association between expansion of TEM cells in PB and changes in ctDNA dynamics at EoT, albeit preliminary, supports ctDNA as a marker for depth and durability of response. Overall, our PD and biomarker observations so far strengthen the rationale of combining glofitamab with englumafusp alfa to drive long-term responses in this heavily pre-treated NHL patient population."

Biomarker • Clinical • IO biomarker • P1 data • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD8 • PD-1

Novel Immunotherapy Combinations in Indolent Lymphoma (SOHO 2025) - P1/2, P2, P3 | "The MITHIC-FL1 Table Overview of BsAb combination studies in patients with FL Trial /NCT Phase Treatment setting Number of patients Description Outcomes CRS Median follow-up EPCORE NHL-2, Arm 2 NCT04663347 Phase 1b/2 Relapse/ refractory 111 subcutaneous epcoritamab with R² ORR: 96% CR: 87% Grade 1 – 2: 46% Grade 3: 2% 25.3 months EPCORE FL1 NCT05409066 Phase 3 Relapse/ refractory 500 subcutaneous epcoritamab with R² vs R² NA NA Jan 2030 27 Grade 1 – 2: 25% (mostly grade 1) NA NCT04246086 Phase 1b Relapse/ refractory mosunetuzumab plus lenalidomide ORR: 92%; CR- 77% CELESTIMO NCT04712097 Phase 3 Relapse/ refractory 400 NA NA mosunetuzumab plus lenalidomide vs rituximab plus lenalidomide NA NCT06453044 Phase 2 NA March 2028 Relapse/ refractory 41 mosunetuzumab and polatuzumab vedotin NA NCT04077723 Phase 1 subgroup englumafusp alfa combined with glofitamab ORR: 91% CR: 80% Relapse/ refractory 134 pts total , 24 in the iNHL Grade 1 – 2: 63%..."

Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Oncology

The bispecific antibody KA-5377, targeting CD19 and 4-1BB, specifically enhances T cell activity against lymphoma (AACR 2025) - "The difference in EC50 (effective concentration for 50% activation) between the CD19-bound and non-bound states is approximately 100-fold, compared to only a 2-fold difference observed with the benchmark bispecific antibody Englumafusp Alfa.When combined with a low concentration of CD3 antibody to stimulate T cell activation, KA-5377 significantly enhances T cell activation and proliferation in co-culture assays using primary T cells isolated from human PBMCs. Toxicity studies are currently ongoing. In conclusion, KA-5377, developed using our nanobody antibody discovery platform, represents a promising preclinical candidate for the treatment of Relapsed/Refractory B-cell lymphoma."

IO biomarker • B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19

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

Clinical relevance of spatially-resolved transcriptional signatures characterizing macrophages from the light and dark zone of the germinal centre (SITC 2024) - P1/2 | "Macrophage signatures (MacroSigs) derived from these regions were evaluated in clinical cohorts of DLBCL treated with R-CHOP or a novel immunotherapy combination. Data from DLBCL patients treated with with Glofitamab and Englumafusp alfa combination were obtained from phase I clinical trial (NCT04077723).Download figure Open in new tab Download powerpoint Abstract 1387 Figure 1 Schematic of GeoMx® DSP WTA workflow (created with BioRender.com)Download figure Open in new tab Download powerpoint Abstract 1387 Figure 2 Spatially-derived MacroSig3/4 (LZ/DZ) stratify for patient survival in DLBCL datasetsDownload figure Open in new tab Download powerpoint Abstract 1387 Figure 3 DZ MacroSigs enriched tumours showed a relative enrichment in T-regulatory cells (Treg)Download figure Open in new tab Download powerpoint Abstract 1387 Figure 4 Association between patient stratification based on LZ- or DZ-MacroSigs and therapy response in a phase 1 trial of the Glofitamab..."

Clinical • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD68

BP41072: A Study to Evaluate the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of Englumafusp Alfa in Combination With Obinutuzumab and in Combination With Glofitamab Following a Pre-Treatment Dose of Obinutuzumab in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma (clinicaltrials.gov) - P1/2 | N=498 | Recruiting | Sponsor: Hoffmann-La Roche | Phase classification: P1 ➔ P1/2 | Trial completion date: Mar 2025 ➔ Mar 2027 | Trial primary completion date: Mar 2025 ➔ Mar 2027

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

ENGLUMAFUSP ALFA (CD19/4-1BBL) COMBINED WITH GLOFITAMAB IS SAFE AND SHOWS HIGH EFFICACY IN PATIENTS WITH R/R AGGRESSIVE B-NHL: FINAL RESULTS OF THE DOSE-ESCALATION PART OF PHASE1 TRIAL BP41072 (EHA 2024) - P1 | "5/10/30mg) in cycles 1/2 after a single obinutuzumabdose (1000mg). These are the first clinical data demonstrating that combining a T-cell engager with a bispecific antibody-likefusion protein delivering a strong costimulatory signal is safe and efficacious in B-NHL pts. A dose expansionstudy is currently underway."

Clinical • P1 data • Anemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Infectious Disease • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Novel Coronavirus Disease • Oncology • Pneumonia • Respiratory Diseases • CD8 • PD-1

Englumafusp alfa/Glofitamab Combo Shows Early Responses in R/R Aggressive non-Hodgkin Lymphoma (OncLive) - P1b | N=498 | NCT04077723 | Sponsor: Hoffmann-La Roche | "The combination of englumafusp alfa and glofitamab (Columvi) demonstrated clinical activity and tolerability across all dose levels examined in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (B-NHL), according to dose-escalation findings of the first-in-human phase 1b BP41072 study (NCT04077723) that were presented during the 2024 EHA Congress. Results showed that, of 83 patients in the second-line and beyond setting, the best overall response (BOR) with the combination was 67.0% and the complete response (CR) rate was 57.0%. In the third-line and beyond setting, these rates were 65.7% and 52.8%, respectively."

P1 data • Diffuse Large B Cell Lymphoma • Follicular Lymphoma

COMBINING CD19-4-1BBL (RO7227166) WITH GLOFITAMAB IS SAFE AND SHOWS EARLY EFFICACY IN PATIENTS SUFFERING FROM RELAPSED OR REFRACTORY B-CELL NON-HODGKIN LYMPHOMA (ICML 2023) - P1 | "After a single obinutuzumab dose (1000 mg), pts started glofitamab step up dosing receiving the first target dose of 30 mg on C2D1. Glofitamab can be safely combined with a costimulatory bispecific antibody (RO7227166) in R/R B-NHL. The safety profile of the combination was mainly driven by glofitamab and we did not detect an additive safety signal from RO7227166."

Clinical • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD8 • TNFRSF9

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

[VIRTUAL] RG6076 (CD19-4-1BBL): CD19-Targeted 4-1BB Ligand Combination with Glofitamab As an Off-the-Shelf, Enhanced T-Cell Redirection Therapy for B-Cell Malignancies (ASH 2020) - P1 | "The preclinical data we report here provide a strong rationale for adding CD19-4-1BBL-mediated T cell signal 2 to glofitamab in the clinic to further boost treatment efficacy and deliver an off-the-shelf, enhanced T cell redirection approach alternative to CAR-T cell therapy. CD19-4-1BBL is currently in clinical trials (NCT04077723)."

IO Biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hepatology • Immune Modulation • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD20 • FCGR2A

[VIRTUAL] Phase 1 Study of CD19 Targeted 4-1BBL Costimulatory Agonist to Enhance T Cell (Glofitamab Combination) or NK Cell Effector Function (Obinutuzumab Combination) in Relapsed/Refractory B Cell Lymphoma (ASH 2020) - P1 | "RO7227166, a CD19 targeted 4-1BBL (CD137) costimulatory agonist has shown synergistic anti‑tumor activity when combined with glofitamab in preclinical models (fig 1). The maximum duration of the study for each participant will be up to 24 months in Part I (excluding survival follow-up) and up to 18 months in Part II and Part III. Tumor biopsies and peripheral blood biomarker analyses will be used to demonstrate MoA and proof of concept of an off the shelf flexible combination option providing signals 1 and 2."

IO Biomarker • P1 data • Hematological Malignancies • Hepatology • Immune Modulation • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD20

CD19 4-1BBL (RO7227166) a Novel Costimulatory Bispecific Antibody Can be Safely Combined with the T-Cell-Engaging Bispecific Antibody Glofitamab in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma (ASH 2022) - P1 | "Pts received 1000mg obinutuzumab 7 days prior to first glofitamab administration to mitigate cytokine release syndrome (CRS). No new safety signals or signs of increased immune-related AEs were detected and the overall safety profile was consistent with that reported from single-agent glofitamab. At doses explored, combination therapy maintains efficacy similar to glofitamab single-agent, and dose escalation continues with additive benefit of the combination expected at higher doses."

Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Immune Modulation • Indolent Lymphoma • Infectious Disease • Inflammation • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Novel Coronavirus Disease • Oncology • Pneumonia • Respiratory Diseases • Septic Shock • CD19 • CD8

A Study to Evaluate the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of RO7227166 in Combination With Obinutuzumab and in Combination With Glofitamab Following a Pre-Treatment Dose of Obinutuzumab Administered in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma (clinicaltrials.gov) - P1 | N=420 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jan 2023 ➔ Mar 2025 | Trial primary completion date: Jan 2023 ➔ Mar 2025

Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD20 • CD8

A Study to Evaluate the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of RO7227166 in Combination With Obinutuzumab and in Combination With Glofitamab Following a Pre-Treatment Dose of Obinutuzumab Administered in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma (clinicaltrials.gov) - P1 | N=362 | Recruiting | Sponsor: Hoffmann-La Roche | Phase classification: P1/2 ➔ P1

Combination therapy • Phase classification • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD20 • CD8

Tumor-Targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-The-shelf therapy (Sci Transl Med) - "...we engineered proteins simultaneously targeting 4-1BB and a tumor stroma or tumor antigen: FAP–4-1BBL (RG7826) and CD19–4-1BBL. In the presence of a T cell receptor signal, they provide potent T cell costimulation strictly dependent on tumor antigen–mediated hyperclustering without systemic activation by FcγR binding. We could show targeting of FAP–4-1BBL to FAP-expressing tumor stroma and lymph nodes in a colorectal cancer–bearing rhesus monkey. Combination of FAP–4-1BBL with tumor antigen–targeted T cell bispecific (TCB) molecules in human tumor samples led to increased IFN-γ and granzyme B secretion. Further, combination of FAP– or CD19–4-1BBL with CEA-TCB (RG7802) or CD20-TCB (RG6026), respectively, resulted in tumor remission in mouse models, accompanied by intratumoral accumulation of activated effector CD8 ⁺ T cells."

Preclinical • Hematological Malignancies • Oncology

A Study to Evaluate the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of RO7227166 in Combination With Obinutuzumab and in Combination With Glofitamab Following a Pre-Treatment Dose of Obinutuzumab Administered in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma (clinicaltrials.gov) - P1/2; N=362; Recruiting; Sponsor: Hoffmann-La Roche; Phase classification: P1 ➔ P1/2; N=207 ➔ 362

Enrollment change • Phase classification • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD20 • CD8

A Study to Evaluate the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of RO7227166 in Combination With Obinutuzumab and in Combination With Glofitamab Following a Pre-Treatment Dose of Obinutuzumab Administered in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma (clinicaltrials.gov) - P1; N=207; Recruiting; Sponsor: Hoffmann-La Roche

Clinical • Combination therapy • New P1 trial • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD20 • CD8

First Report of grapevine red globe virus in grapevines in Washington State. (PubMed, Plant Dis) - "To further confirm infection by GRGV, total RNA was extracted from two asymptomatic Pinot gris vines previously tested positive in HTS using Spectrum Total RNA isolation kit and subjected to reverse transcription-PCR using primers specific to the replicase polyprotein gene of the virus (RG4847F: 5'-TGGTCTGTTGTTCGCATCTT-3' and RG6076R: 5' CGGAAGGGGAAGCATTGATCT-3', Cretazzo et al., 2017)...Although GRGV can cause asymptomatic infections in grapevines (Martelli et al. 2002), the economic importance of GRGV as single or coinfections with other viruses needs to be examined to assess the potential significance of the virus to grape production and grapevine certification programs."

Journal • Oncology

Newly added product (clinicaltrials.gov) - P1, Non-Hodgkin's lymphoma

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