Clinical Utility of Combined Tissue and Plasma Next-Generation Sequencing in Patients with Advanced, Treatment-Naïve, Non-Small-Cell Lung Cancer

Introduction Tissue and plasma-based NGS have complementary roles in patients with advanced NSCLC. However, whether there is any added clinical value in combining both methods in treatment naïve patients remains unclear. Methods We retrospectively collected clinical and genomic data from 275 patients with treatment-naïve advanced NSCLC that had undergone plasma-based NGS at diagnosis in our institution. We analysed patient data in two separate cohorts, each assessed with a different plasma-based NGS method: Cohort 1 (n=127, Guardant360), and cohort 2 (n=148, FoundationACT/FoundationOne Liquid CDx). Ninety-five patients (75%) in cohort 1 and 108 patients (73%) in cohort 2 underwent concurrent amplicon-based tissue NGS testing locally. Results Forty-three patients in cohort 1 (34%) and 49 patients in cohort 2 (33%) harboured ESCAT I-II targetable driver alterations. The addition orthogonal biopsy (tissue to liquid, or liquid to tissue) offered no significant clinical value in cases with ESCAT I-II targetable drivers already detected by one method. In contrast, adding orthogonal biopsy incremented the detection of ESCAT I-II targetable drivers not only in cases with uninformative testing (undetectable ctDNA, unavailable/inadequate tissue), but also in about 5% of the patients with seemingly informative but driver undetected molecular results. The prevalence of ESCAT I-II targetable drivers in plasma was significantly higher in patients with adenocarcinoma, ≤20 pack/year smoking history, and abdominal metastases. Conclusions Our study suggests that the addition of sequential orthogonal biopsy should be considered whenever an ESCAT I-II targetable driver has not been detected by the initial method, including cases with seemingly informative molecular analysis.