Phase Ib multicenter study of anti-TIM-3 (S095018/Sym023) in combination with anti-PD-1 (Sym021) in patients with advanced/metastatic recurrent biliary tract cancer

  • J Immunother Cancer. 2026 Mar 13;14(3):e012344. doi: 10.1136/jitc-2025-012344.
Francois Ghiringhelli  1 ,  Richard Kim  2 ,  Teresa Macarulla  3 ,  Irene Moreno  4 ,  Albiruni Abdul Razak  5 ,  Jordi Rodon Ahnert  6 ,  Chih-Yi Liao  7 ,  Sarah Lindsey Davis  8 ,  Amit Mahipal  9 ,  Thomas Marron  10 ,  Judith Raimbourg  11 ,  Hélène Kaplon  12 ,  Julia Geronimi  12 ,  Najah Harouki  12 ,  Christelle Rodrigues  12 ,  Pauline Darcel  12 ,  Janus Schou Jakobsen  13 ,  Niels Skartved  13 ,  Rikke Hald  13 ,  Daleen Lopez-Ravnborg  13 ,  Peng He  14 ,  Xenophon Ianopoulos  14 ,  Vasileios Askoxylakis  14 ,  Nehal Lakhani  15
Affiliations
  • 1. Centre Georges-Francois Leclerc, Dijon, Bourgogne-Franche-Comté, France [email protected].
  • 2. H Lee Moffitt Cancer Center and Research Institute Department of Gastrointestinal Oncology, Tampa, Florida, USA.
  • 3. Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • 4. Start Madrid- CIOCC, Centro Integral Oncologico Clara Campal, Madrid, Spain.
  • 5. Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Canada.
  • 6. University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 7. Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medicine Comprehensive Cancer Center, Chicago, Illinois, USA.
  • 8. Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 9. UH Seidman Cancer Center, Cleveland, Ohio, USA.
  • 10. Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 11. Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Saint Herblain, France.
  • 12. Servier, Gif-sur-Yvette, France.
  • 13. Symphogen A/S, Ballerup, Denmark.
  • 14. Servier, Boston, Massachusetts, USA.
  • 15. Developmental Therapeutics, START Midwest, Grand Rapids, Michigan, USA.
PMID: 41825935 DOI: 10.1136/jitc-2025-012344
Abstract

Background: T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) is an inhibitory receptor linked to decreased antitumor activity of immune cells. S095018 is a human anti-TIM-3 IgG2 antibody that blocks the binding of phosphatidyl serine to TIM-3. Sym021 is a humanized IgG1 antibody that inhibits the binding of programmed cell death protein-1 (PD-1) to its ligands programmed death-ligand 1 (PD-L1) and PD-L2.

Methods: S095018 in combination with Sym021 was tested in patients with advanced/metastatic biliary tract cancers (BTC) whose disease progressed under treatment with at least 1 line of systemic therapy and who had not received prior treatment with PD-(L)1 inhibitors (NCT04641871). Patients received 3 mg/kg of Sym021 and 10 mg/kg of S095018 once every 2 weeks. Primary endpoints included overall response rate and incidence/severity of adverse events. Key secondary endpoints included pharmacokinetics, immunogenicity assessment, progression-free survival (PFS) and overall survival (OS).

Results: 35 patients with stage IV BTC received S095018 in combination with Sym021. A partial response was achieved in 2 patients (5.7%) and stable disease in 11 patients (31.4%) for a disease control rate of 37%; 4 patients were not evaluable for response. Median PFS and OS were 1.9 months (90% CI 1.8 to 3.7) and 13.4 months (90% CI 8.2 to 27.1), respectively. The most common treatment-emergent adverse events of any grade included fatigue, pruritus, infusion-related reaction, and increases in amylase (8.6% each). Exploratory biomarker analyses in paired tumor biopsies showed an increase in intratumoral CD8 T-cell density and an upregulation of gene signatures related to interferon-γ signaling, antigen presentation, and T-cell activation with treatment without, however, clear association with efficacy endpoints.

Conclusions: Dual PD-1/TIM-3 inhibition was tolerable but exhibited modest antitumor activity in patients with advanced/metastatic recurrent BTC who had not received prior anti-PD-(L)1 treatment.

Keywords
Biliary Tract Cancer; Immune Checkpoint Inhibitor; Immunotherapy.
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