Recent trials have shown a clinical efficacy of checkpoint inhibitors combined with radiotherapy for a subset of patients with pancreatic ductal adenocarcinoma (PDAC). However, predictive biomarkers are needed. Multiple proteins are released into the bloodstream due to cancer and immune reactions, and several circulating proteins have been associated with response to immunotherapy in other cancers. We investigated 90 immuno-oncology (I-O) related serum proteins in 78 patients with PDAC treated with nivolumab with or without ipilimumab combined with radiotherapy in a randomized phase 2 study (CheckPAC, NCT02866383).
Proteins were measured in serum samples collected at baseline and after 2 months of treatment using Olink Target 96 I-O panel (Olink Proteomics, Uppsala, Sweden). Serum protein levels were correlated with efficacy data using Wilcoxon test or t-test. Survival was analyzed with univariate and multivariate Cox-regression adjusting for performance status, Glasgow prognostic score, bilirubin, study arm, and weight loss. An unadjusted p-value of 0.05 was considered significant.
Patients with clinical benefit (partial response (n=7) or stable disease (n=15)) had significantly higher levels of fas ligand (FASLG) and galectin 1 (Gal-1), and decreased C-C motif chemokine (CCL) 4 compared to patients without clinical benefit. High Gal-1 and FASLG and low angiopoietin-2 and mucin-16 were associated with longer progression-free survival in univariate analysis. In multivariate analysis, the association remained significant for Gal-1 (Hazard ratio (HR) = 0.25, confidence interval (CI) 0.12-0.56, p<0.001), and borderline significant for FASLG (HR=0.52, CI: 0.26-1.04, p=0.06). For 14 proteins, an increase in protein level during treatment was associated with progressive disease, whereas a decreasing level of 3 proteins (including CCL4) was associated with clinical benefit. Changes in FASLG and Gal-1 were not associated with clinical benefit rate.
The study identified Gal-1 and possibly FALSG as potential novel predictive biomarkers of immunotherapy efficacy in patients with PDAC. The results need to be confirmed in future studies.
NCT02866383.
The authors.
Bristol Myers Squibb.
I. Chen: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Institutional, Research Grant: Roche, Bristol Myers Squibb, Celgene, Genis, Varian Medical Systems. All other authors have declared no conflicts of interest.