Clinical utility of next-generation sequencing-based ctDNA testing for common and novel ALK fusions

•Liquid biopsy for plasma ctDNA NGS is capable of partner agnostic detection of ALK fusions.•A subset of patients can be matched to ALK-directed therapy based on plasma ctDNA testing.•PON1, a novel ALK fusion partner, was detected in plasma in a lung cancer patient. Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited. Materials and Methods: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response. Results: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p