RG7827 / Roche - LARVOL DELTA

FAP-targeted 4-1BBL trimeric costimulation amplifies T-cell activation and antitumor efficacy of a CEA-directed T-cell engager in MSS colorectal cancer (AACR 2026) - P1 | "Full T-cell activation, however, requires integrated signaling through the TCR-CD3 complex and costimulatory pathways such as those mediated by the 4-1BB receptor, expressed on antigen-primed T cells. We evaluated the combination of cibisatamab with escalating doses of FAP-4-1BBL, a fibroblast activation protein (FAP)-dependent 4-1BB agonist, in an open-label Phase 1b study (BP42675; NCT04826003) in patients with MSS mCRC who had progressed after ≥2 prior lines of therapy. The combination of cibisatamab and FAP-4-1BBL demonstrated a manageable safety profile. These data suggest that FAP-targeted 4-1BB costimulation can potentiate the antitumor activity of CEA-directed T-cell bispecific antibodies. The results support further development of tumor-localized 4-1BB agonists in combination with T-cell-engaging therapies for MSS mCRC and other non-inflamed ("cold") tumors."

Clinical • Colorectal Cancer • Oncology • Solid Tumor • CCR7 • CD8 • CEACAM5 • PD-1 • TNFRSF9

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 | Terminated | Sponsor: Hoffmann-La Roche | Completed ➔ Terminated; Study was closed early as the sponsor decided not to continue development of certain treatment combinations.

Trial termination • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • PD-L1

HARNESSING THE BONE MARROW STROMA IN AML: FAP-TARGETED COSTIMULATORY AGONISTS POTENTIATE T-CELL BISPECIFIC ANTIBODY ACTIVITY AND PRESERVE T-CELL FITNESS (EHA 2026) - "Efficacy of WT1-TCB + FAP-4-1BBL or FAP-OX40 was evaluated in short-term coculture assays (4 days) 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...Summary/Conclusion In conclusion, combining a WT1-targeting TCB with a FAP-targeted 4-1BB agonist significantly enhanced T-cell-mediated anti- leukemic activity and preserved T-cell fitness during continuous TCB stimulation. By directing costimulation to the bone marrow niche via FAP, this strategy addresses both the insufficient costimulatory ligand expression on AML blasts and the immunosuppressive bone marrow niche, representing a promising approach to overcome the barriers limiting TCB efficacy in AML."

Bispecific • IO biomarker • Stroma • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Nephrology • Solid Tumor • Wilms Tumor • CD86 • FAP • TNFSF4 • WT1

Cibisatamab and FAP-4-1BBL in microsatellite-stable colorectal cancer: a phase 1b trial. (PubMed, Nat Med) - P1 | "Patients received cibisatamab with escalating doses of FAP-4-1BBL weekly or every 3 weeks after obinutuzumab pretreatment to mitigate anti-drug antibody formation. These findings demonstrate the feasibility of combining tumor antigen-directed T cell engagement with localized co-stimulation, with evidence of immune activation and preliminary antitumor activity supporting further clinical development. ClinicalTrials.gov identifier: NCT04826003 ."

IO biomarker • Journal • P1 data • Colorectal Cancer • Cytomegalovirus Infection • Gastroenterology • Gastrointestinal Disorder • Immunology • Oncology • Solid Tumor • CD8 • CEACAM5 • IFNG • IL2RA • TNFRSF9

Precision modeling of tumor antigen-specific T-cell responses in humanized mice for preclinical assessment of cancer immunotherapies. (PubMed, J Immunother Cancer) - "This adaptable and physiologically relevant model provides a platform to dissect the complex interplay between human tumors, immune cells, and immunotherapies and has the potential to significantly improve the translation of preclinical findings to the clinic."

Journal • Preclinical • Oncology • CD40 • PD-1

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."

Bispecific • 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 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed

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

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 | N=54 | Completed | Sponsor: Hoffmann-La Roche | Phase classification: P1/2 ➔ P1

Phase classification • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • CEACAM5 • CSF2

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 | Trial completion date: May 2026 ➔ Oct 2025 | Trial primary completion date: Oct 2024 ➔ Oct 2025

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

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