# Circulating free DNA as a predictive biomarker for response to nivolumab and platinum-based chemotherapy in metastatic esophageal adenocarcinoma: a prospective pilot study

## TL;DR

This study shows that early changes in circulating free DNA can predict treatment response and survival in patients with metastatic esophageal adenocarcinoma receiving chemoimmunotherapy.

## Contribution

The study introduces cfDNA kinetics as a novel non-invasive biomarker for treatment response prediction in metastatic esophageal adenocarcinoma.

## Key findings

- A cfDNA Day 30/Baseline ratio <0.4 was associated with significantly improved progression-free and overall survival.
- Early decline in cfDNA levels correlated with better treatment response in patients.
- High tumor mutational burden independently predicted increased treatment response.

## Abstract

Reliable biomarkers are urgently needed to predict response to immune checkpoint inhibitors in metastatic esophageal adenocarcinoma (mEAC). This study evaluated early circulating free DNA (cfDNA) dynamics as a predictor of treatment response and survival in patients receiving platinum-based chemotherapy plus Nivolumab.

In this prospective pilot study, 95 patients with mEAC were treated with Nivolumab and platinum-based chemotherapy. Plasma cfDNA levels were measured at baseline, Day 15, and Day 30 using digital droplet PCR. The primary outcome was objective treatment response; secondary outcomes included progression-free survival (PFS) and overall survival (OS). Tumor mutational burden (TMB), PD-L1 expression, liver metastasis, and ECOG status were also assessed.

Patients with a cfDNA Day 30/Baseline ratio <0.4 had significantly improved median PFS (11 vs. 4 months) and OS (14 vs. 7 months) compared to those with ratios >0.8 (p for trend <0.001). Early decline in cfDNA correlated with treatment response. High TMB (≥10 mut/Mb) was independently associated with increased response (adjusted OR: 2.5, 95% CI: 1.2–5.2, p=0.015). ECOG >1 was inversely associated with response (adjusted OR: 0.35, p=0.01). PD-L1 expression and liver metastasis were not significantly predictive.

Early cfDNA kinetics—particularly a Day 30/Baseline ratio <0.4—strongly predicted response and survival in mEAC patients receiving chemoimmunotherapy. cfDNA monitoring offers a promising non-invasive tool for early treatment stratification and response assessment in this population.