Exploring plasma cell-free RNA biomarkers for predicting immune checkpoint inhibitor efficacy in gastric cancer: a translational sub-study of the KSCC VOYAGER phase II trial.

BACKGROUND

Immune checkpoint inhibitors (ICI) are used to treat unresectable advanced or recurrent gastric cancer; however, reliable predictive biomarkers remain limited. This study aimed to identify biomarkers for predicting ICI efficacy using two independent cohorts.

METHODS

Plasma-derived cell-free RNA (cfRNA) transcriptome analysis was performed on pretreatment plasma samples from 34 patients in the VOYAGER phase II trial of the early induction of nivolumab monotherapy as third line or later. Candidate genes were identified using differentially expressed gene analyses based on three indicators: disease progression during treatment, best response, and progression-free survival ≥ 6 months. These candidates were validated by immunohistochemistry in tumor tissue from an independent cohort of 64 patients treated with nivolumab. Additional immune analyses were conducted using The Cancer Genome Atlas and CIBERSORT.

RESULTS

Receptor-interacting serine/threonine-protein kinase 4 (RIPK4) was consistently upregulated in non-responders across all analyses. In the validation cohort, RIPK4-positive patients receiving nivolumab as first-line therapy exhibited significantly shorter progression-free survival (hazard ratio 2.62, 95% confidence interval 1.08-6.37). RIPK4 expression was also associated with a lower disease control rate (30% vs. 68%, p = 0.005). TCGA-based analyses showed that tumors with high RIPK4 exhibited significantly reduced PDCD1 and CD8A expression alongside a lower fraction of M2 macrophages and CD8+ T cells, thereby suggesting a non-inflamed tumor microenvironment.

CONCLUSIONS

Elevated RIPK4 expression in plasma-derived cfRNA and tumor tissue was associated with a poor response to nivolumab, suggesting that RIPK4 may serve as a biomarker of ICI efficacy in gastric cancer. Further studies are warranted to validate its clinical utility.