T-cell invigoration to cell-free DNA ratio associated with anti-PD-1 response in gastric or gastro-esophageal junction adenocarcinoma: VOYAGER trial.

Background: Previous melanoma research suggests that host immune status and tumor burden impact anti-programmed cell death protein 1 (PD-1) therapy efficacy, favoring patients with low tumor burden and minimal T-cell exhaustion. Patients and methods: We conducted a phase II, multicenter, single-arm (VOYAGER) trial to assess early induction of nivolumab monotherapy as third-line or later treatment in patients with gastric adenocarcinoma showing response or stable disease as per RECIST v1.1 during prior chemotherapy. Biomarker analyses evaluated associations between nivolumab efficacy, T-cell activation, and cell-free DNA (cfDNA) as a tumor burden surrogate. Activated T cells (Ki67+ PD-1+ CD8+ T cells) were measured by flow cytometry of peripheral blood mononuclear cells. Results: The study met its primary endpoint with a progression-free survival (PFS) rate at 6 months of 35.7% [80% confidence interval (CI) 26.4% to 45.1%]; median PFS and overall survival (OS) were 4.0 (95% CI 2.3-5.7) months and 10.9 (95% CI 9.9-16.0) months, respectively. No new safety signals were observed. Biomarker analyses revealed that baseline T-cell invigoration rate was associated with both response rate (RR) and prognosis. Baseline cfDNA also exhibited an association with prognosis, but not with RR. Moreover, the ratio of baseline T-cell invigoration to baseline cfDNA was strongly associated with RR ( Conclusions: This study not only demonstrated that early induction of nivolumab as a later-line regimen is an alternative strategy but also identified clinically available predictors for PD-1 blockade therapy.