Use of liquid biomarkers to track fibrotic changes in pancreatic cancer patients treated with combined immunotherapy and radiotherapy (CheckPAC).

762 Background: Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, with low treatment response and < 1 year median overall survival (OS) time. The poor response to immune checkpoint inhibitors (ICIs) in PDAC is linked to its highly fibrotic and immunosuppressive tumor microenvironment (TME), characterized by deposition of extracellular matrix by cancer-associated fibroblast (CAF), including various collagens. This deposition of collagens releases quantifiable fragments of procollagens in the blood, with potential as biomarkers of CAF activity. In this study, we investigated the prognostic, predictive and pharmacodynamic potential of type III collagen deposition (PRO-C3), type XI collagen deposition (PRO-C11), and release of matrix-bound TGF-β (TGF-β LAP) in patients with treatment-refractory, metastatic PDAC receiving combination radiotherapy and ICIs. Methods: PRO-C3, PRO-C11, and TGF-β LAP were measured in serum samples from 84 patients enrolled in the CheckPAC trial (NCT02866383). Patients were treated with stereotactic body radiotherapy (SBRT) and nivolumab (n = 41) or SBRT and nivolumab + ipilimumab (n = 43). Samples were obtained prior to treatment (baseline), at initiation of second treatment cycle, and at the end of regular treatment. Baseline biomarker levels were dichotomized at the 75 th percentile based on results from previous studies. Biomarkers were assessed for pharmacodynamic effects across treatment types and predictive potential was evaluated relative to treatment response (RECIST 1.1). Kaplan-Meier analysis and Cox regression were used to evaluate OS; Fisher’s exact test assessed treatment response. Results: At baseline, high levels of PRO-C3 and PRO-C11 were significantly associated with short OS (HR=2.75, 95% CI 1.62-4.66, p<0.001 and HR=1.86, 95% CI 1.10-3.15, p=0.02, respectively). Longitudinally, an increase in TGF-β LAP levels was significantly associated with treatment non-response (PD) already from the second cycle of treatment (p = 0.02). Furthermore, a reduction in PRO-C3 and PRO-C11 levels at end of treatment were significantly associated with treatment response (p = 0.009 and p = 0.05, respectively) and decreased risk of dying (HR=0.33, p=0.002 and HR=0.41, p=0.01, respectively), suggesting decreased fibrosis in responders and an increased immunosuppression in non-responders. Conclusions: Serological changes in fibrosis-related biomarkers correlated with treatment response and survival among patients with PDAC receiving immunotherapy and radiotherapy. Fibrosis-related liquid biomarkers may help evaluate TME activity and inform future clinical decision-making in PDAC.