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

Abstract

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.

Fig. 1. Risk stratification according to liquid biopsy results and clinicopathological features in the whole population.

A Kaplan–Meier curve for PFS of the study population stratified into three risk groups based on their individual score in the nomogram (Supplementary Figs. 1 and 2). Factors affecting PFS in multiple regression models were: cfDNA concentration in plasma at baseline, maxVAF at T2, increase (∆T2–T1) of cfDNA, and PD-L1 expression. B Kaplan–Meier curves for the OS of the study population stratified into three risk groups based on their individual score in the nomogram (Supplementary Figs. 1 and 2). Factors affecting OS in multiple regression models were: cfDNA at baseline, increased (∆T2–T1) of cfDNA, maxVAF at T2, histology and PD-L1 expression.

Fig. 2. Risk stratification according to liquid biopsy results and clinicopathological features among patients treated with first-line ICIs and high PD-L1 expression.

A Kaplan–Meier curve for PFS (A) of patients treated with first-line pembrolizumab and stratified into three risk groups based on their individual scores in the nomogram. Factors affecting PFS in multiple regression models were: maxVAF at T2 and increase (∆T2–T1) of cfDNA. B Kaplan–Meier curves for the OS of patients treated with first-line pembrolizumab and stratified into three risk groups based on their individual scores in the nomogram. Factors affecting OS in multiple regression models were: maxVAF at T2 and increase (∆T2–T1) of cfDNA.