Clinical utility of combined plasma and tissue NGS in patients with advanced, treatment-naïve, Non-small Cell Lung Cancer

The incremental clinical value of performing both tissue and plasma next-generation sequencing (NGS) to detect actionable alterations (AA) in advanced non-small cell lung cancer (aNSCLC) has not been comprehensively assessed. We aimed to study the clinical utility of performing both techniques in patients with newly diagnosed aNSCLC. We conducted a study with two aNSCLC cohorts, prospectively assessed with tissue and plasma NGS at diagnosis. For tissue analysis, Oncomine Focus Assay was performed. Guardant360 CDx and FoundationOne Liquid CDx were used in cohort 1 (N=127) and cohort 2 (N=149), respectively. We considered AA according to ESCAT I-III levels. Undetectable ctDNA and unavailable tissue were considered non-informative results. AA were found in 50/127 (39%) and 65/149 (44%) patients in cohorts 1 and 2, respectively (Figure 1). Thirty of 127 patients (24%) in cohort 1 and 22/149 (15%) in cohort 2 received targeted therapy. In cohort 1, AA were detected in both plasma and tissue in 27/50 (54%) patients, only in plasma in 14/50 (28%) and only in tissue in 9/50 (18%). In the 14 cases with AA only detected in plasma, 11 had non-informative tissue results, but 3 had informative tissue results (1 EGFR and 1 KRAS G12C mutations detected in plasma but not in tissue). In the 9 cases with AA only detected in tissue, 3 had uninformative plasma results, but 6 had informative plasma results (1 ALK fusion, 1 ERBB2 amplification, 1 EGFR and 2 KRAS G12C mutations detected in tissue but not in plasma). In cohort 2, AA were detected in both assays in 28/65 (43%) patients, only in plasma in 22/65 (34%) and only in tissue in 15/65 (23%). In the 22 cases with AA only detected in plasma, 11 had non-informative tissue results, but 11 had informative tissue results (1 RET and 1 ALK fusions, 3 ERBB2 alterations, 2 KRAS G12C mutations detected in plasma but not in tissue). In the 15 cases with AA only detected in tissue, 9 had uninformative plasma results, but 6 had informative plasma results (3 EGFR mutations, 1 ROS1 fusion and 2 ERBB2 amplifications detected in tissue but not in plasma). Combined tissue and plasma NGS can increase the detection of AA in patients with newly diagnosed aNSCLC when AA are not detected by one of these assays. Due to discordant data observed, plasma NGS should be considered when AA are not detected by tissue, and viceversa.