This prospective study explores the prognostic value of circulating tumor DNA (ctDNA) and positron emission tomography/computed tomograpy (PET/CT) in unresectable locally advanced non-small cell lung cancer (LA-NSCLC) treated with definitive chemoradiotherapy (CRT). The discovery set includes 62 patients, with 62 baseline and 53 post-CRT plasma samples. PET/CT is performed at baseline, and 33 patients undergo mid-treatment scans after 40 Gy. Baseline ctDNA is detected in 71.0% of patients. Pre-treatment ctDNA concentration correlates with total metabolic tumor volume (TMTV) (p <
0.001) and total lesion glycolysis (TLG) (p = 0.001) but not treatment response or survival. However, patients with undetectable ctDNA and low TMTV show significantly longer progression-free survival (PFS) (34.2 vs 10.1 months, p = 0.027). Post-CRT, ctDNA is detected in 47.2% of patients, while ctDNA concentration (p = 0.005) and variant allele frequency (VAF) (p = 0.005) significantly decline. Undetectable post-CRT ctDNA associates with longer PFS (p <
0.001) and overall survival (OS) (p = 0.001). Higher ∆TMTV correlates with improved PFS and OS. Similar findings were obtained in a test of 19 patients. These results highlight post-CRT ctDNA and ∆TMTV as robust prognostic markers, potentially identifying patients who may forgo ICI consolidation.