Prospective comparison of liquid biopsy to standard of care tissue testing in metastatic, non-squamous, non-small cell lung cancer (NSCLC) patients (pts)

Abstract

Background: Targeted therapy improves clinical outcomes in pts with advanced NSCLC harboring specific genetic alterations. Guidelines recommend tissue-based assessment of markers, but this approach may be limited by access to sufficient tissue and tumor heterogeneity, making it difficult to identify all pts who may benefit from these treatments. An alternative approach is to assess somatic mutations in circulating cell-free tumor DNA (cfDNA). The aim of this study is to demonstrate that cfDNA is non-inferior to tissue-based genotyping in detecting clinically actionable tumor biomarkers in pts with newly diagnosed metastatic non-squamous NSCLC. Trial design: This is a multi-center, prospective, single-cohort study. Major inclusion criteria are: (1) metastatic, biopsy proven, non-squamous NSCLC, (2) candidate for first line systematic therapy, (3) no prior targeted therapy. Peripheral blood (20 mL) is collected for cfDNA sequencing prior to and 2 weeks after treatment initiation and at the time of disease progression (maximum 12 months follow-up). cfDNA sequencing is performed using Guardant360, a comprehensive next-generation assay (Guardant Health, Inc., Redwood City, CA USA). Pre-treatment tissue samples archived at local sites are centrally analyzed. Pts are treated according to investigator standard of care criteria. Tumor response is assessed centrally per RECIST v1.1 on pts who received targeted therapy. Primary endpoint is the detection rate, in either blood or tissue, of a clinically actionable somatic biomarker, defined as mutations in EGFR, BRAF, MET and ERBB2, copy number of MET and rearrangement of the ROS1, RET and ALK genes. A total of 182 pts are needed to test a 10% non-inferiority margin. We assumed a 20% detection rate, with a 19% discordant pairs and 10% dropout rate. The one-sided asymptotic test has 90% power, at a nominal significance level of 5%. Secondary objectives are to compare turn-around time, time to treatment initiation, rates of insufficient tissue for testing or tumor not detected in cfDNA, and tumor response to targeted therapies. Genomically acquired resistance to targeted therapies is also investigated.