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 - BP42675

Start Date21 Jul 2021

Sponsor / Collaborator

Roche Nederland BV

NCT04826003

/ CompletedPhase 1/2

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 With High CEACAM5 Expression

This is an open-label, multicenter, Phase Ib study to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) in the weekly (QW) and/or every 3 weeks (Q3W) regimens, safety, tolerability, PK, immunogenicity, PD profile and to evaluate preliminary anti-tumor activity of RO7122290 in combination with cibisatamab Q3W after pretreatment with obinutuzumab, in participants with previously treated metastatic, microsatellite-stable colorectal adenocarcinoma with high CEACAM5 expression

Start Date14 Jul 2021

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

100 Clinical Results associated with RG-7827

100 Translational Medicine associated with RG-7827

100 Patents (Medical) associated with RG-7827

Literatures (Medical) associated with RG-7827

04 Aug 2023·Cancer discovery

FAP-Targeted 4-1BB Agonist Tamps Down Advanced Tumors.

Article

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.

10 May 2023·Science translational medicineQ1 · MEDICINE

A first-in-human study of the fibroblast activation protein–targeted, 4-1BB agonist RO7122290 in patients with advanced solid tumors

Q1 · MEDICINE

Article

Author: Davydov, Iakov I ; Rohrberg, Kristoffer ; Krieter, Oliver ; Azaro, Analia ; Moreno, Victor ; McIntyre, Christine ; Sanmamed, Miguel F ; Duarte, José ; Nüesch, Eveline ; Ooi, Chiahuey ; Moreno, Irene ; Ponz-Sarvisé, Mariano ; Martinez Garcia, Maria ; Chesne, Evelyne ; Hernandez, Tatiana ; Bustamante, Mariana ; Ceppi, Maurizio ; Melero, Ignacio ; Guarin, Ernesto ; Tabernero, Josep ; Spanggaard, Iben ; Tanos, Tamara ; Cañamero, Marta ; Rodriguez-Vida, Alejo ; Calvo, Emiliano

This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent ( n = 65) or in combination with a 1200-milligram fixed dose of the anti–programmed death-ligand 1 (anti–PD-L1) antibody atezolizumab given every 3 weeks ( n = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose was identified. The pharmacokinetic profile of RO7122290 suggested nonlinearity in elimination. The observed changes in peripheral and tissue pharmacodynamic (PD) biomarkers were consistent with the postulated mechanism of action. Treatment-induced PD changes included an increase in proliferating and activated T cells in peripheral blood both in the single-agent and combination arms. Increased infiltration of intratumoral CD8 + and Ki67 + CD8 + T cells was observed for both treatment regimens, accompanied by the up-regulation of T cell activation genes and gene signatures. 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.

News (Medical) associated with RG-7827

05 Feb 2025

·www.echemi.com

Roche Reports CHF 60.5 Billion Revenue in 2024 with Focus on Oncology and R&D Adjustments

On January 30, Roche announced its financial results for 2024, reporting total revenue of CHF 60.495 billion (approximately $66.4 billion with a conversion rate of 1 CHF = 1.0981 USD), representing a 7% year-on-year growth. However, net income declined to CHF 9.187 billion (about $10.1 billion), a significant drop of 19%. The company invested CHF 13.042 billion (around $14.3 billion) in research and development, accounting for 21.6% of total revenue. Oncology continued to be the primary focus for R&D, along with substantial investments in immunology, cardiovascular, renal, and metabolic fields. Roche's pharmaceutical business generated CHF 46 billion (about $50.7 billion), marking an 8% increase, while the diagnostics division saw revenues of CHF 14.3 billion (approximately $15.7 billion), up 7%. The pharmaceutical segment remains the main source of Roche's profits. The company's pharmaceutical portfolio includes targeted therapies across five key areas: oncology, immunology, neuroscience, hematology, and ophthalmology. The ophthalmology sector showed remarkable growth in 2024, with sales reaching CHF 4 billion, reflecting a 44% increase. All other therapeutic areas also maintained positive growth trajectories. The drug Vabysmo (faricimab), launched in early 2022, continued to be a major growth driver, with sales of CHF 3.864 billion (about $4.243 billion) driven by increasing demand across all regions. Vabysmo is approved for three major retinal diseases, including wet age-related macular degeneration, diabetic macular edema, and retinal vein occlusion. Looking ahead, Roche's pipeline is robust, featuring 71 new molecular entities (NMEs) and a total of 122 projects. However, the financial report indicated that the company has reduced ten projects in Q4 2024, primarily in early development stages. Notably, Roche made significant cuts to its TIGIT antibody RG6058 pipeline, including two Phase III trials, two Phase II trials, and one Phase I trial. Several early-stage projects were also removed from the pipeline, including: A Phase I study of the FAP/4-1BB bispecific antibody RG7827 for solid tumors. A Phase I study of the HER2/CD3 bispecific antibody RG6194 for breast cancer. Additional Phase I projects targeting various solid tumors. The TIGIT monoclonal antibody RG6058, which had been the first TIGIT antibody to enter Phase III trials globally. Roche also removed two Phase II trials for the TIGIT antibody targeting metastatic head and neck squamous cell carcinoma and non-small cell lung cancer, alongside two Phase III trials. In recent updates, Roche faced setbacks with the TIGIT antibody in 2024. The SKYSCRAPER-06 study, which evaluated the combination of tiragolumab, Tecentriq, and chemotherapy against pembrolizumab and chemotherapy for locally advanced non-squamous NSCLC, did not meet its primary endpoint, showing a hazard ratio of 1.27 for progression-free survival. Currently, Roche's TIGIT antibody pipeline includes five ongoing Phase III studies, focusing on NSCLC, esophageal cancer, and liver cancer. Looking forward, Roche anticipates the potential for over seven new molecular entities with peak sales exceeding CHF 3 billion, along with four additional entities with peak sales between CHF 2 billion and 3 billion.

Phase 1Drug ApprovalFinancial StatementPhase 2Phase 3

30 Jan 2025

·www.fiercebiotech.com

Roche drops HER2 bispecific, Xencor-partnered cytokine from early-phase pipeline

Roche also reported the removal of a pair of phase 1 candidates managed by its Chugai subsidiary. \n Roche has given two early-phase bispecifics the heave-ho, ending work on a HER2xCD3 prospect and an IL-15 candidate it picked up from Xencor.The drugmaker removed (PDF) the molecules from its phase 1 pipeline as part of its fourth-quarter clearout. The HER2 asset, known as both RG6194 and runimotamab, was in development in breast cancer. Vir Biotechnology recently reported phase 1 data on its rival HER2 bispecific VIR-5818.The IL-15 candidate, efbalropendekin alfa, was designed to drive the expansion and activation of T cells and natural killer cells by fusing IL-15 to its alpha receptor and Xencor’s bispecific Fc domain. Xencor revised the terms of the deal with Roche’s Genentech late in 2023, opting out of a deal to split costs and agreeing to success-related fees that could have totaled $600 million. Roche also included RG7827, a 4-1BBxFAP bispecific antibody, on the list of the candidates removed from its phase 1 pipeline. However, a Roche spokesperson clarified that the action relates to the company’s decision to end work on the CEAxCD3 bispecific candidate cibisatamab.“Following the discontinuation of cibisatamab, the phase 1 dose escalation study evaluating the combination of cibisatamab with FAP-4-1BBL is discontinued. This decision does not affect any potential future research and development of FAP-4-1BBL beyond the combination with cibisatamab,” the Roche spokesperson said.Roche stopped studying cibisatamab in combination with its checkpoint inhibitor Tecentriq in colorectal cancer patients last year but continued to test the asset with its 4-1BBxFAP bispecific. At the time, Teresa Graham, CEO of Roche Pharmaceuticals, said “we\'ve seen encouraging early data that would lead us to believe that further study is necessary or warranted.” Roche has pursued a multifront attack on FAP, studying CD40 and DR5 bispecifics, respectively RG6189 and RG7386, and the immunocytokine RG7461, but dropped those assets over time. The 4-1BB bispecific RG7827, also known as RO7122290, recently completed phase 1/2 trials in urothelial and colorectal cancers.Amgen returned a 4-1BBxFAP bispecific to Molecular Partners almost three years ago, but FAP remains a target of interest for multiple companies. Molecular Partners is still developing the FAPxCD40 bispecific MP0317, Novartis is working (PDF) on radioligand therapies, Genmab has a FAPxDR4 candidate in phase 1 and Avacta Therapeutics is expanding development of its peptide-drug conjugate.Roche also reported the removal of a pair of phase 1 candidates managed by its Chugai subsidiary. One of the assets was a glypican-3xCD3 T cell-redirecting antibody for treatment of solid tumors. The other axed Chugai candidate was SPYK04, a RAF-MEK molecular glue that the Japanese drugmaker removed (PDF) from its pipeline in October.

Phase 1License out/inPDC

01 Feb 2024

·www.fiercebiotech.com

Roche, pipeline bulging from deal spree, axes 8 oncology and neurology programs to speed up R&D

Roche’s clear-out was accompanied by an influx of other assets. Roche has removed eight phase 1 and 2 oncology and neurology candidates from its pipeline as part of a set of “trade-offs” intended to “increase the overall portfolio value and speed up development.” In the fourth quarter (PDF), Roche removed eight drug candidates and replaced them with eight different prospects, shifting the balance of its pipeline away from neurology and, to a lesser extent, oncology and toward immunology, cardiovascular and metabolism in the process. The number of neurology prospects fell from 18 to 12, although one of those was moved to another part of the pipeline. CEO Thomas Schinecker said the the resources will be shifted "to projects we want to accelerate." He also foreshadowed similar pipeline cuts to come in the first quarter during a fourth quarter earnings call Thursday. Basmisanil is one of the candidates Roche is kicking to the curb. The drugmaker trialed the GABAA α5 receptor negative allosteric modulator in ischemic stroke and schizophrenia patients from 2016 to 2019. The discovery of an EEG biomarker of dup15q, a developmental disorder, spurred interest in treating the syndrome by reducing GABA activity in the brain and led Roche to start enrolling patients in a phase 2 trial in 2022. ClinicalTrials.gov lists the study as recruiting, but Roche removed the asset from its pipeline. Roche also axed balovaptan, a small-molecule vasopressin V1A receptor antagonist that previously made it to phase 3 in autism spectrum disorder only to fail to move the needle. The drugmaker tried again in the aftermath of the failure, kicking off a phase 2 study in post-traumatic stress disorder. Roche finished that trial last year and promptly removed balovaptan from its pipeline. News of the other neurology changes preceded the fourth-quarter update. AC Immune said Roche had returned the Alzheimer’s disease prospects crenezumab and semorinemab last month, and details of the decision to drop Angelman syndrome candidate rugonersen emerged via the patient community last year. On the oncology side, Roche removed three phase 1 candidates from the pipeline. The drugmaker dealt a second blow to the hopes of treating solid tumors by targeting FAP. Having already stopped studying a FAP-IL-2v candidate, Roche removed the solid tumor FAP-CD40 prospect RG6189 from its pipeline in the fourth quarter. A phase 1b trial of a FAP-4-1BBL candidate, RG7827, is continuing. The other two axed oncology assets are the EGFRvIIIxCD3 bispecific antibody RG6156, which Roche was studying in brain cancer, and another bispecific designed to bind to HLA-G on tumor cells and CD3 on T cells. Roche’s clear-out was accompanied by an influx of other assets, including candidates acquired through the takeovers of Carmot Therapeutics and Telavant. A longer-term bet delivered a clinical candidate, too, with Roche moving a covalent inhibitor of WRN, the synthetic lethal target at the heart of a $135 million deal with Vividion Therapeutics, into phase 1.

Phase 2Phase 1PROTACsClinical Trial Failure

100 Deals associated with RG-7827

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic Colorectal Carcinoma	Phase 2	United States	Hoffmann-La Roche, Inc.	14 Jul 2021
Metastatic Colorectal Carcinoma	Phase 2	Denmark	Hoffmann-La Roche, Inc.	14 Jul 2021
Metastatic Colorectal Carcinoma	Phase 2	Netherlands	Hoffmann-La Roche, Inc.	14 Jul 2021
Metastatic Colorectal Carcinoma	Phase 2	South Korea	Hoffmann-La Roche, Inc.	14 Jul 2021
Metastatic Colorectal Carcinoma	Phase 2	Spain	Hoffmann-La Roche, Inc.	14 Jul 2021
Metastatic Colorectal Carcinoma	Phase 2	United Kingdom	Hoffmann-La Roche, Inc.	14 Jul 2021
Metastatic Microsatellite Stable Colorectal Carcinoma	Phase 2	United States	Hoffmann-La Roche, Inc.	14 Jul 2021
Metastatic Microsatellite Stable Colorectal Carcinoma	Phase 2	Denmark	Hoffmann-La Roche, Inc.	14 Jul 2021
Metastatic Microsatellite Stable Colorectal Carcinoma	Phase 2	Netherlands	Hoffmann-La Roche, Inc.	14 Jul 2021
Metastatic Microsatellite Stable Colorectal Carcinoma	Phase 2	South Korea	Hoffmann-La Roche, Inc.	14 Jul 2021

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


286 (SITC2020)	Phase 1	Advanced Malignant Solid Neoplasm FAP-positive	14	RO7122290 5 mg	zvoqxmauoi(dqoansvque) = jwgaapfmva lzdapwzgvw (vjgetadsyj, 4.1)	-	09 Nov 2020
				RO7122290 45 mg	zvoqxmauoi(dqoansvque) = chfcondapl lzdapwzgvw (vjgetadsyj, 4.9)
ESMO2020	Phase 1	Advanced Malignant Solid Neoplasm	-	RO7122290	ftjnnpooge(dwsppvemsf) = AEs were generally mild to moderate (i.e., G1-2) across both parts. Most common AEs ≥ G3 in Part A were asthenia (6.5%), AST elevation and pneumonia (each 4.8%), whereas pneumonia, pneumonitis (each 10.3%), neutro- and lymphocytopenia (each 7.7%) were most frequent in Part B. DLTs were febrile neutropenia G3 (45 mg), CRS G3 (130 mg) and pneumonitis G3 (500 mg plus ATZ); a MTD was not reached. rovhpbksho (roywypcalk )	-	18 Sep 2020
				RO7122290 + Atezolizumab

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