Background: NSCLC often manifests multifocally and individual tumor loci may differ in their mutational landscape, complicating genomic analysis by tissue biopsies. Liquid biopsy may have the potential to overcome this challenge. Our study aimed to explore the potential of circulating tumor DNA (ctDNA) for predicting and monitoring treatment response and identifying potential resistance mutations.

Methods: 22 patients with advanced NSCLC receiving first line immune checkpoint inhibition (ICI) by pembrolizumab with no actionable EGFR mutations or ALK-rearrangements and PD-L1 ? 50% were prospectively included. Blood plasma samples were collected before treatment initiation (baseline) and at time of radiological progression. Molecular responders (MR) were defined by a decrease in ctDNA, non-responders (MNR) by an increase. Sequencing and analysis of the samples was performed using the Illumina TruSight Oncology 500 ctDNA method.

  
Results: ctDNA was detected in 19 of 22 patients with a median variant allele frequency, defined as ratio of ctDNA to cell free DNA, of 3.21% at baseline and, under treatment, 1.45% at progression. Median progression free survival (PFS) was 165 days. 90% of patients having a PFS above median were MRs. At the first CT-evaluation, 71% of MRs had radiological stable disease or partial response. Overall survival of MRs was significantly longer (p=0,0001). Looking into potential resistance mutations, we found in three patients at least one ?acquired? mutation at time of progression. 

Conclusion: Our study supports the utility of NGS-based ctDNA measurements to monitor treatment response and resistance mutations in a majority of ICI-treated advanced NSCLC patients.