The Journal of Liquid Biopsy · Published 2026-07-21 · DOI 10.1016/j.jlb.2026.100484
Diego Enrico, Gisela Vargas, Gabriela Wulfson, Carmen Pupareli, Florencia Tsou, Delfina Peralta Tanco, Federico Waisberg, Lucas Coradini, Milena Revelli Ling, Matías Chacón, Roberto Borea, Christian Rolfo, Claudio Martín
Background: 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. Methods: 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). Results: 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. Conclusions: 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.
Abstract from DOAJ. Public domain (CC0 1.0).
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Enrico, D., Vargas, G., Wulfson, G., et al. (2026). Early tumor-informed circulating tumor DNA (ctDNA) dynamics correlate with response to first-line advanced NSCLC treated with pembrolizumab ± chemotherapy. The Journal of Liquid Biopsy. https://doi.org/10.1016/j.jlb.2026.100484