Ultra-sensitive, tumor-informed ctDNA profiling in pembrolizumab-treated esophagogastric cancer patients predicts clinical responses.

To explore whether ultra-sensitive circulating tumor DNA (ctDNA) profiling enables early prediction of treatment response and early 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. All 25 patients evaluated were ctDNA-positive at baseline. Minimal residual disease (MRD) events varied from 406,067 down to 1.5 parts per million (PPM) of ctDNA with a median limit of detection of 2.03 PPM. ctDNA dynamics were highly correlated with changes in tumor size (ρ = 0.59, = 7.3×10). Lack of early molecular response (lack of ctDNA decrease) was associated with worse overall survival (OS) (HR 6.6, 95% CI 1.8-24.1, = 0.005) and progression-free survival (PFS) (HR 15.4, 95% CI 2.7-87.0, = 0.002). Lack of molecular clearance of ctDNA was associated with worse OS (HR 6.9, 95% CI 1.5-30.8, p = 0.012) and PFS (HR 19.2, 95% CI 2.4-152.8, 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.