Cibisatamab and FAP-4-1BBL in microsatellite-stable colorectal cancer: a phase 1b trial

Journal article

We evaluated cibisatamab, a carcinoembryonic antigen (CEA)-directed CD3 T cell-engaging bispecific antibody, in combination with FAP-4-1BBL, a fibroblast activation protein (FAP)-targeted 4-1BB ligand providing tumor-localized co-stimulation, in an open-label phase 1b dose-escalation study in patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) progressing after two or more prior therapies. Patients received cibisatamab with escalating doses of FAP-4-1BBL weekly or every 3 weeks after obinutuzumab pretreatment to mitigate anti-drug antibody formation. The primary endpoint was safety; secondary endpoints included antitumor activity, pharmacokinetics and biomarker analyses. Among 52 treated patients, the combination showed a manageable safety profile. Dose-limiting toxicities occurred in 2 out of 52 patients (3.8%). Cytokine release syndrome (CRS) occurred in 30 out of 52 patients (57.7%; grade ≥3: 2 out of 52, 3.8%) and was manageable; after a cycle 1 cibisatamab dose reduction to 60 mg, serious CRS occurred in 4 out of 27 patients (14.8%; grade ≥3: 0 out of 27). Gastrointestinal toxicities consistent with CEA-directed T cell engagement were observed. Colitis occurred in 7 out of 52 patients (13.5%), including immune-mediated enterocolitis and one fatal cytomegalovirus colitis. No maximum tolerated dose of FAP-4-1BBL was established. Confirmed partial responses were observed in 7 out of 52 patients (13.5%). Pharmacodynamic analyses demonstrated systemic immune activation, including increased IFNγ, soluble CD25, soluble 4-1BB (CD137) and activated, proliferating CD8+ T cells. Paired tumor biopsies showed increased intratumoral CD8+ and CD8+Ki67+ T cell infiltration. 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 .

Authors: Melero, I; Tanos, T; Calvo Aller, E; Qvortrup, C; van Dongen, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Medicine
• Publication date: 2026-04-20
• Acceptance date: 2026-03-30
• DOI: 10.1038/s41591-026-04380-z
• EISSN: 1546-170X
• ISSN: 1078-8956
• Language: English
• Keywords: Clinical trial; Phase (matter); Phases of clinical research; Colorectal cancer