Monitoring treatment response using an ultra-sensitive ctDNA assay in advanced esophagogastric cancer patients

To explore whether ultra-sensitive circulating tumor DNA (ctDNA) profiling enables earlier prediction of treatment response and detection of disease progression, we applied NeXT Personal, an ultra-sensitive bespoke tumor-informed liquid biopsy platform, to profile tumor samples from the KeyLargo study, a phase II trial in which metastatic esophagogastric cancer (mEGC) patients received capecitabine, oxaliplatin, and pembrolizumab. A total of 24 patients were evaluated, and all were ctDNA-positive at baseline. ctDNA levels varied from 406,067 down to 1.5 parts per million (PPM) with a median limit of detection of 2.03 PPM. ctDNA dynamics were highly correlated with changes in tumor size (ρ = 0.59, p = 7.3 × 10^{- 9}). Lack of early molecular response (50% or greater decrease in ctDNA levels at first available time point after 30 days, C2D1 or C4D1) was associated with worse overall survival (OS) (HR 4.5, 95% CI 1.2-16.7, p = 0.02) and progression-free survival (PFS) (HR 10.4, 95% CI 2.2-49.8, p = 0.003). Lack of molecular clearance of ctDNA was associated with worse OS (HR 7.1, 95% CI 1.6-31.7, p = 0.01) and PFS (HR 19.9, 95% CI 2.5-158.2, p = 0.005). Molecular progression (ctDNA increase) preceded imaging-derived progression by a median lead time of 65 days. These results suggest that ultra-sensitive liquid biopsy approaches could improve treatment decision-making for mEGC patients receiving chemotherapy and immunotherapy.