Longitudinal liquid biopsy predicts clinical benefit from immunotherapy in advanced non-small cell lung cancer.

High heterogeneity in clinical benefit characterizes the use of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). We prospectively enrolled 113 advanced NSCLC patients treated with ICIs and performed liquid biopsy at the time of ICI start (T1), after 3 weeks (T2) and at the time of radiological evaluation (T3). Molecular variables were associated with outcome endpoints: cfDNA quantification, its dynamic change (∆T2-T1), variant allele frequency (VAF) of the gene with the highest frequency detected at baseline with NGS (maxVAF) and its dynamic change (∆T2-T1). At multivariate analysis, PD-L1 negativity, T1 cfDNA, cfDNA increase (∆T2-T1), and T2 VAF were significantly associated with shorter progression-free survival (PFS); PD-L1 negativity, squamous histology, T1 cfDNA, cfDNA (∆T2-T1) increase, and T2 maxVAF affected overall survival (OS). Among high PD-L1 expressing patients treated in first-line, elevated T2 maxVAF and cfDNA increase (∆T2-T1) correlated with worse PFS; higher T2 maxVAF and cfDNA increase (∆T2-T1) with worse OS. Derived integrated models were used to build nomograms and categorize different risk groups.