ctFE (tumor-naïve ctDNA burden metric) predicts OS/PFS early during chemoRT for LA/oligometastatic NSCLC

In the prospective Phase II NCT03916419 trial, circulating tumor fraction estimate (ctFE)—a machine learning-derived composite of ctDNA burden from a clinically available, tumor-naïve assay—was measured at baseline and mid-treatment (day 10–14) in unresectable stage IIB–III NSCLC receiving MR-guided hypofractionated chemoradiation followed by immunotherapy (n=26). Baseline ctFE stratified both OS (HR 5.93, p=0.005) and PFS (HR 11.08, p<0.001), and remained strongly prognostic at mid-treatment (OS HR 7.08; PFS HR 12.06; both p<0.001), outperforming Max VAF and “ctDNA detectable vs not” approaches. Early ctFE dynamics further separated three molecular response groups with median OS 60.8 vs 13.0 vs 2.9 months (p<0.001), and the same fixed ctFE threshold validated in external real-world cohorts: locally advanced chemoRT (LA-RW; n=94) and oligometastatic radiotherapy (OM-RW; n=309); clinically, this aims to refine risk beyond today’s one-size-fits-all consolidation approach (e.g., PACIFIC-style durvalumab after CRT improved PFS vs placebo, median ~16.8 vs 5.6 months).