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

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.