RG7827 / Roche - LARVOL DELTA

Augmenting T-cell bispecific antibody therapy in AML through co-stimulatory agonists (AACR 2025) - "Accordingly, we evaluated the combination of the AML-targeting Wilms tumor 1 (WT1)-TCB with co-stimulatory agonistic bispecific antibodies, targeting 4-1BBL or OX40 and fibroblast activation protein (FAP) expressed on bone marrow stromal cells.Efficacy of WT1-TCB + FAP-4-1BBL or FAP-OX40 was evaluated in co-culture assays with human AML cell lines or murine Ba/F3 cell lines expressing hu4-1BBL or huCD86, healthy donor T cells and an NIH-3T3 fibroblast cell line expressing FAP...We conclude, that combining a WT1-targeting TCB with a 4-1BB agonist significantly enhanced T-cell activity against AML cell lines and primary AML samples. Notably, this positive immune modulation persisted in long-term cultures, counteracting T-cell exhaustion caused by continuous TCB stimulation."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Wilms Tumor • CD86 • FAP • WT1

MORPHEUS mUC: Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients With Urothelial Carcinoma (MORPHEUS-UC) (clinicaltrials.gov) - P1/2 | N=272 | Active, not recruiting | Sponsor: Hoffmann-La Roche | N=645 ➔ 272

Enrollment change • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • PD-L1

4-1BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy to treat murine breast tumor models. (PubMed, J Immunother Cancer) - "Increased FAP expression in the TME as a result of radiotherapy can be exploited to target agonist 4-1BB immunotherapy to malignant tumor lesions using an FAP-4-1BBL antibody fusion protein."

IO biomarker • Journal • Preclinical • Breast Cancer • Colorectal Cancer • Oncology • Solid Tumor • Transplantation • CAFs • CD8 • FAP • IFNAR1 • IFNG

BP42675: Study To Evaluate Safety, Pharmacokinetics, Pharmacodynamics, And Preliminary Anti-Tumor Activity Of RO7122290 In Combination With Cibisatamab With Obinutuzumab Pre-Treatment (clinicaltrials.gov) - P1/2 | N=54 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed | N=80 ➔ 54

Enrollment change • Trial completion • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • CEACAM5

MORPHEUS mUC: Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients With Urothelial Carcinoma (MORPHEUS-UC) (clinicaltrials.gov) - P1/2 | N=645 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting | Trial completion date: Nov 2027 ➔ May 2026

Enrollment closed • Trial completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • PD-L1

4–1BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy to treat murine breast tumor models (SITC 2024) - "Conclusions Increased FAP expression in the TME as a result of radiotherapy can be exploited to target agonist 4-1BB immunotherapy to malignant tumor lesions using a FAP-4-1BBL antibody fusion protein. Ethics Approval The experimental protocols were approved by the Ethics Committee of the University of Navarra (CEEA037-20 and CEAAE27-23) in accordance with European Council Guidelines All patients signed informed consent forms for their tissues to be used in this study."

IO biomarker • Preclinical • Breast Cancer • Colorectal Cancer • Oncology • Solid Tumor • CAFs • CD8 • FAP • IFNAR1 • IFNG • TNFRSF9

Combining mathematical modeling, in vitro data and clinical target expression to support bispecific antibody binding affinity selection: a case example with FAP-4-1BBL. (PubMed, Front Pharmacol) - "In this work, a workflow to select binding affinities for bispecific antibodies that integrates preclinical in vitro data, mathematical modeling and simulation, and knowledge on target expression in the patient population, is provided. The early implementation of this approach can increase the probability of success with cancer immunotherapy in clinical development."

IO biomarker • Journal • Preclinical • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FAP • TNFRSF9

Enhanced pharmacodynamic effects upon combination of cibisatamab and FAP-4-1BBL in 3L+ mMSS CRC patients (ESMO 2024) - P1, P1/2, P1b, P1b/2a, P2 | "Clinical trial identification: BP42675 "an open-label, multicenter, phase Ib study to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of RO7122290, a fibroblast activation protein-a (FAP) targeted 4-1BB ligand (CD137L), in combination with cibisatamab with obinutuzumab pre-treatment, in participants with previously treated, metastatic, microsatellite-stable colorectal adenocarcinoma". The enhanced clinical PD effects of the combination of cibisatamab and FAP-4-1BBL demonstrate the additive effects of costimulation to signal 1 only providers such as TCBs in a tumor considered largely insensitive to cancer immunotherapies. These encouraging results advocate for further studies exploring the combination of T cell engagers such as TCBs with FAP-4-1BBL, as this approach holds the potential to unlock new frontiers in cancer treatment."

Clinical • IO biomarker • PK/PD data • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • CD4 • CD8 • IFNG • IL2RA • IL6

Study To Evaluate Safety, Pharmacokinetics, Pharmacodynamics, And Preliminary Anti-Tumor Activity Of RO7122290 In Combination With Cibisatamab With Obinutuzumab Pre-Treatment (clinicaltrials.gov) - P1/2 | N=80 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jul 2025 ➔ Dec 2024 | Trial primary completion date: Jul 2025 ➔ Dec 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CEACAM5

Study To Evaluate Safety, Pharmacokinetics, Pharmacodynamics, And Preliminary Anti-Tumor Activity Of RO7122290 In Combination With Cibisatamab With Obinutuzumab Pre-Treatment (clinicaltrials.gov) - P1/2 | N=80 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CEACAM5

A model-based approach leveraging in vitro data to support dose selection from the outset: A framework for bispecific antibodies in immuno-oncology. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "We integrated in vitro data with mathematical modeling to characterize the pharmacology of FAP-4-1BBL as a function of trimeric complex formation when combined with the T-cell engager cibisatamab. Depending on the dosing schedule and FAP-4-1BBL plasma: tumor distribution, doses between 2 and 145 mg could lead to maximum trimeric complex formation in the clinic. Due to the expected variability in both pharmacokinetic and FAP expression in the patient population, we predict that detecting a clear dose-response relationship would remain difficult without a large number of patients per dose level, highlighting that mathematical modeling techniques based on in vitro data could aid dose selection."

Immuno-oncology • IO biomarker • Journal • Preclinical • Oncology • FAP

FAP-Targeted 4-1BB Agonist Tamps Down Advanced Tumors. (PubMed, Cancer Discov) - "Findings from a phase I study of the bispecific antibody RO7122290, which targets CD137 and the fibroblast activity protein, show that it produces responses in patients with advanced solid tumors-without the liver toxicity associated with earlier therapies targeting CD137. Additional research evaluating RO7122290 in combination with atezolizumab or other immune agents is planned."

Journal • Metastases • Hepatology • Oncology • Solid Tumor • TNFRSF9

Partners-in-Crime: Co-Stimulation via 4-1BB or CD28 to Boost the Efficacy of T Cell Bispecifics (PEGS 2023) - "The presentation will cover an overview and update on preclinical properties of solid and heme tumor co-stimulators including FAP-4-1BBL, CD19-4-1BBL, and CD19-CD28 in active clinical development in combination with cibisatamab and glofitamab, respectively."

Clinical • Oncology

A first-in-human study of the fibroblast activation protein-targeted, 4-1BB agonist RO7122290 in patients with advanced solid tumors. (PubMed, Sci Transl Med) - "Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors."

IO biomarker • Journal • Metastases • P1 data • Febrile Neutropenia • Hematological Disorders • Immune Modulation • Neutropenia • Oncology • Pneumonia • Solid Tumor • CD8 • FAP • TNFRSF9

4-1BBL agonist targeted to fibroblast activation protein α synergizes with radiotherapy in murine breast tumor (AACR 2023) - "Robust immune memory was observed in re-challenge experiments.Conclusion. Our data provides a proof-of-concept and mechanistic insights pertaining the therapeutic efficacy of the bispecific FAP-41BBL fusion protein combined with local radiotherapy."

IO biomarker • Preclinical • Breast Cancer • Oncology • Solid Tumor • CD8 • FAP

Study To Evaluate Safety, Pharmacokinetics, Pharmacodynamics, And Preliminary Anti-Tumor Activity Of RO7122290 In Combination With Cibisatamab With Obinutuzumab Pre-Treatment (clinicaltrials.gov) - P1/2 | N=80 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Oct 2024 ➔ Jul 2025 | Trial primary completion date: Oct 2024 ➔ Jul 2025

Combination therapy • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • CEACAM5 • CSF2 • IFNG • IL6 • TNFA

MORPHEUS mUC: Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients With Urothelial Carcinoma (MORPHEUS-UC) (clinicaltrials.gov) - P1/2 | N=645 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jun 2026 ➔ Aug 2027 | Trial primary completion date: Jul 2023 ➔ Nov 2024

Trial completion date • Trial primary completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • PD-L1

[VIRTUAL] Stroma-immune landscape in lymphoma: new mechanisms of immunosuppression and therapeutic targeting (AACR 2021) - "Moreover, lymphoma-FRCs upregulated expression of inhibitory PD-1 ligands that reduced the anti-tumor cytolytic activity of CD8+ T cells, a T cell bispecific antibody (CD20-TCB, glofitamab) and anti-CD19 CAR T cells in our coculture models.To overcome the immunosuppressive activity of DLBCL-FRCs, we investigated the use of CD20-TCB in combination with stroma-targeting immunocytokine fusion protein drug (FAP-IL2v, RG7461) or costimulatory fusion protein (FAP-4-1BBL, RG7827). In addition, the ability of immune- /stroma- targeted combination immunotherapy to trigger anti-tumor activity and CD8+ T cell retention within the FRC-TME was demonstrated using 3D precision-cut lymph node slice-based organotypic cultures of DLBCL and other B cell malignancies.In conclusion our data reveal that lymphoma cells actively reprogram FRCs that acquire altered immunoregulatory function which prevents effective T cell motility and suppresses the anti-tumor function of cytolytic T cells...."

IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20 • CD8

[VIRTUAL] Combination of TYRP1-TCB, a novel T cell bispecific antibody for the treatment of melanoma, with immunomodulatory agents (AACR-II 2020) - "Bispecific antibodies like blinatumomab have been approved for hematologic malignancies but positive benefit in solid tumors has been more challenging to demonstrate...Furthermore, the combination with immunomodulatory agents like FAP-IL2v and FAP-4-1BBL molecules demonstrated enhanced efficacy as compared to the respective single agents. These preclinical data support the clinical evaluation of TYRP1 targeted CD3 bispecific antibody as a single agent and in combination in metastatic relapsed/refractory melanoma patients."

IO Biomarker • Late-breaking abstract • Melanoma • Oncology • Solid Tumor • Melanosome • Tyrosinase

[VIRTUAL] Tumor-bearing non-human primates: An unrivaled model for translational cancer immunology research (AACR-II 2020) - "Because of the similar tumor stroma biology shared between humans and rhesus macaques, TBMs are particularly well suited to test FAP-targeting agents. We anticipate that testing cancer immunotherapy compounds in TBMs could be of high predictability for clinical behavior."

IO Biomarker • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor