What question did this study set out to answer?

The aim is to assess the predictive potential of extracellular matrix biomarkers in response to immunotherapy combined with radiotherapy in metastatic biliary tract cancer.

June 14, 2026Open Access

Extracellular matrix biomarkers of T-cell infiltration and tumor fibrosis predict response to nivolumab ± ipilimumab with SBRT in biliary tract cancer: insights from the CheckPAC trial

Key Points

The aim is to assess the predictive potential of extracellular matrix biomarkers in response to immunotherapy combined with radiotherapy in metastatic biliary tract cancer.
Measured biomarkers (C4G, PRO-C3, PRO-C6, reC1M, C3M, C4M) in serum of 61 metastatic BTC patients in the CheckPAC trial (NCT02866383).
Patients received SBRT with nivolumab or nivolumab/ipilimumab, with biomarker assessments at baseline and day 60.
Evaluated associations of baseline and on-treatment changes with overall survival and clinical benefit.
Higher baseline PRO-C3 and reC1M correlated with shorter overall survival (p < 0.05) and lack of clinical benefit.
C4G levels increased significantly in patients with clinical benefit (p < 0.001) while remaining unchanged in others.
Low PRO-C3 and increased C4G at day 60 indicated favorable survival, even in patients with no RECIST-defined benefit (p < 0.001).

Abstract

BACKGROUND: Biliary tract cancer (BTC) is an uncommon malignancy with limited treatment options and poor prognosis. BTC is typically characterized by a desmoplastic, collagen-rich extracellular matrix (ECM), which has been linked to immune exclusion and therapy resistance. Although immune checkpoint inhibitors (ICI) combined with gemcitabine/cisplatin have become first-line treatment for advanced BTC, durable responses are rare, and predictive biomarkers for immunotherapy are lacking. We investigated the pharmacodynamic and predictive potential of liquid, ECM-derived biomarkers reflecting cytotoxic T-cell activity (granzyme B-degraded type IV collagen C4G) and fibrotic activity (pro-peptides of type III PRO-C3 and VI PRO-C6 collagens, matrix metalloprotease-degraded type I reC1M, III C3M, and IV collagens C4M) in patients with metastatic BTC receiving combined immunotherapy and radiotherapy. METHODS: Biomarkers (C4G, PRO-C3, PRO-C6, reC1M, C3M, and C4M) were measured in serum from 61 patients with metastatic BTC enrolled in CheckPAC (NCT02866383), treated with stereotactic body radiotherapy (SBRT) combined with nivolumab (n = 19) or nivolumab/ipilimumab (n = 42). Biomarkers were assessed at baseline and day 60. Associations of baseline levels and on-treatment changes with overall survival (OS) and clinical benefit rate were evaluated; longitudinal analyses used a landmark approach. RESULTS: Higher baseline PRO-C3 and reC1M were associated with lack of clinical benefit (p < 0.05) and shorter OS (p < 0.05). In multivariable Cox regression adjusting for CA 19 - 9, ECOG performance status, and modified Glasgow Prognostic Score, PRO-C3 remained independently associated with OS. Longitudinally, C4G increased from baseline to day 60 in all patients with clinical benefit (p < 0.001), whereas no consistent changes were observed among patients without clinical benefit. For the landmark analyses, C4G increase was associated with clinical benefit (p = 0.007) and longer OS (p = 0.0045). Patients with low PRO-C3 and increased C4G at day 60 showed the most favorable survival, including a subgroup without RECIST-defined clinical benefit (p < 0.001). CONCLUSIONS: Serological biomarkers reflecting tumor fibrosis (PRO-C3) and cytotoxic T-cell infiltration (C4G) were associated with clinical benefit and OS and showed pharmacodynamic changes during therapy in patients with metastatic BTC treated with SBRT plus ICI. These biomarkers enable tracking of pharmacodynamic response to ICI, while independent validation is necessary to ensure their predictive utility in immunotherapy.

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