Prospective Multicenter Study Evaluating a Combined Circulating Tumor DNA and Circulating Tumor RNA Liquid Biopsy in...

To evaluate the performance of a circulating tumor DNA (ctDNA) and circulating tumor RNA (ctRNA) liquid biopsy, LiquidHALLMARK (LHM), compared with tissue next-generation sequencing (NGS) and Guardant360 CDx (G360 ctDNA) liquid biopsy for biomarker detection in metastatic nonsquamous non-small cell lung cancer.

This multicenter, prospective study (ClinicalTrials.gov identifier: NCT04703153) enrolled patients across the United States and Singapore. Patients were tested with tissue NGS, LHM, and G360 ctDNA. The primary objective was noninferiority of LHM ctDNA to tissue NGS and G360 ctDNA. Secondary analyses included turnaround time (TAT), overall response rate (ORR), and progression-free survival (PFS), with exploratory analysis of the clinical utility of ctRNA.

LHM ctDNA (48.2%) detected 11.4% fewer biomarker-positive patients than tissue NGS (59.6%) and did not meet noninferiority criteria. Compared with tissue NGS, LHM ctDNA and G360 ctDNA were concordant in 72.1% and 66.1% of patients, establishing noninferiority of LHM ctDNA to G360 ctDNA (P = .002). TAT was shorter for LHM ctDNA than for tissue NGS (mean 9.7 v 21.7 days; P < .001). ORR/PFS was similar in patients receiving targeted therapy based on all three assays. Addition of ctRNA increased the diagnostic yield of tissue NGS-confirmed gene rearrangements by 28.6% relative to LHM ctDNA and all actionable biomarkers by 15.6% relative to G360 ctDNA. LHM ctDNA and ctRNA (51/68) detected 8.8% more biomarker-positive patients than G360 ctDNA (45/68), demonstrating superiority of LHM ctDNA and ctRNA (P = .001).

LHM ctDNA is noninferior to G360 ctDNA, but not tissue NGS. Treatment outcomes based on liquid biopsy are comparable with those based on tissue NGS. Incorporation of ctRNA into LHM ctDNA improves the diagnostic yield of actionable, tissue NGS-confirmed gene rearrangements.