Early tumor-informed circulating tumor DNA (ctDNA) dynamics correlate with response to first-line advanced NSCLC...

Immune checkpoint inhibitors (ICIs), alone or combined with chemotherapy, constitute the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) without actionable oncogenic drivers. However, radiologic response assessment has limitations in capturing early biological treatment effects. Tumor-informed circulating tumor DNA (ctDNA) monitoring has emerged as a promising biomarker for early evaluation of treatment efficacy during immunotherapy.

We conducted a prospective, single-center, longitudinal observational study including patients with stage IV NSCLC treated with first-line pembrolizumab with or without platinum-based chemotherapy between December 2021 and December 2024. Personalized, tumor-informed ctDNA assays (Signatera™, Natera, Inc.) were designed from tumor tissue and matched normal blood samples and applied to serial plasma samples collected at baseline (prior to ICI initiation) and every six weeks on-treatment. Early ctDNA dynamics were assessed from baseline to the first on-treatment assessment (six weeks post-treatment initiation) and were correlated with radiologic response assessed by RECIST v1.1, objective response rate (ORR), and progression-free survival (PFS).

Fifteen patients were enrolled; baseline ctDNA positivity was observed in 13 (87%) patients. Among patients with ctDNA positivity, 11 (85%) experienced a molecular response characterized by ctDNA decrease (n = 1) or clearance (n = 10), while 2 (15%) showed an increase. Early molecular response was strongly associated with radiologic response, with a significantly higher ORR among patients with ctDNA clearance or decrease compared with those with ctDNA increase (91% vs 0%, p = 0.038). Early ctDNA change correlated with percentage change in target lesion size (Spearman R = 0.81, p < 0.001). Longitudinal monitoring demonstrated sustained ctDNA clearance or decrease in patients with durable disease control, while ctDNA positivity preceded radiologic progression. Patient-level survival analysis showed longer progression-free survival intervals predominantly among patients with early ctDNA clearance or decrease.

Early clearance or decrease in ctDNA levels strongly predicted radiographic response in advanced NSCLC treated with first-line pembrolizumab with or without chemotherapy. ctDNA dynamics may complement radiological assessment and support more personalized, timely, and biologically informed treatment decisions in advanced NSCLC.