Background: Molecular profiling of tumor tissue is the gold standard for treatment decision making in advanced non-small cell lung cancer. Results may be delayed or unavailable due to insufficient tissue samples or prolonged wait times for biopsy, pathology assessment and testing. We piloted the use of plasma molecular testing as part of the initial diagnostic work-up for patients with suspected advanced lung cancer (NCT04863924). Methods: Patients with radiologic evidence of advanced lung cancer referred to the lung rapid diagnostic program underwent plasma circulating tumor DNA (ctDNA) testing using InVisionFirst-Lung, a next-generation sequencing (NGS) assay targeting 37 genes. Standard tissue testing was performed with comprehensive NGS (Oncomine). The primary endpoint was time to treatment in stage IV NSCLC patients compared to an historical pre-COVID-19 cohort (2018-9). Secondary endpoints included actionable targets identified in plasma, % of patients starting targeted therapy based on liquid biopsy and result turnaround time (TAT). Results: Between July 1 to December 31, 2021, 60 patients were enrolled. Median age was 70 years (range 33-91), 52% were female, 57% Caucasian, 48% never smokers. Of these, 73% had NSCLC, 12% small cell, 10% non-lung pathology and 5% declined tissue biopsy. Of 44 NSCLC patients, 5 (11%) had early-stage disease and underwent curative therapy. Most stage IV patients (79%) had systemic treatment. Median time to treatment initiation in the study cohort was 34 days (n = 31, range 10-90) versus 62 days (n = 101, range 13-159) in the historical cohort (p<0.0001). Two thirds (N = 23) of stage IV NSCLC patients had actionable alterations identified, (30% in current/ex-smokers); 18 started targeted therapy including 10 based on plasma results before tissue results were available. Median TAT was 7 days for plasma from blood draw to reporting (range 4-14) and 26 days for tissue molecular testing (range 11-42), p<0.0001. Concordance was high between plasma and tissue testing (70%). Liquid biopsy identified actionable alterations for 3 patients not identified by tissue NGS. In 4 cases, plasma testing failed to identify actionable alterations detected in tissue, due to undetectable plasma ctDNA. Conclusions: Liquid biopsy in the initial diagnostic workup of patients with suspected advanced NSCLC leads to faster molecular results and shortens time to treatment compared to tissue testing alone. Supplementing the current standard of tissue molecular testing with a plasma-first approach during the diagnostic work up of patients with suspected advanced lung cancer may increase access to precision medicine and improve patient outcomes. Clinical trial information: NCT04863924.