Brief Report: Prospective Trial of Pembrolizumab Monotherapy in Metastatic NSCLC Evaluating Circulating Tumor DNA as a Surrogate Biomarker of Response.

Brief Report: Prospective Trial of Pembrolizumab Monotherapy in Metastatic NSCLC Evaluating Circulating Tumor DNA as a Surrogate Biomarker of Response. JTO clinical and research reports van 't Erve, I., Blanchard, I., Pagtama, J. Y., Holmes Tisch, A. J., Alizadeh, A. A., Ramchandran, K., Wakelee, H. A., Padda, S. K., Diehn, M., Neal, J. W. 2025; 6 (9): 100877

Abstract

Immune checkpoint inhibitors provide clinical benefit to a subset of patients with metastatic NSCLC, yet the reliable prediction of long-term outcomes remains challenging. We conducted a prospective phase 2 clinical trial to evaluate circulating tumor DNA (ctDNA) as a surrogate biomarker for early clinical response to pembrolizumab monotherapy (NCT02955758). Tumor-informed targeted sequencing of pretreatment and early on-treatment plasma ctDNA in 25 patients with metastatic NSCLC was performed. On-treatment ctDNA response, defined as at least a threefold ctDNA variant allele frequency decrease after three cycles of pembrolizumab versus baseline, was able to predict with 100%, 66%, and 100% accuracy partial response, stable disease, and progressive disease radiologic response, respectively. Molecular response was also correlated with progression-free survival. This study confirms the potential clinical utility of early on-treatment ctDNA-based response evaluation in patients treated with immune checkpoint inhibitors, creating the opportunity for early treatment intervention in nonresponders.

View details for DOI 10.1016/j.jtocrr.2025.100877

View details for PubMedID 40893177

View details for PubMedCentralID PMC12396422