Advanced NSCLC treatment guidelines recommend testing patients for genomic biomarkers to access over 30 FDA-approved targeted therapies. Challenges in NSCLC molecular testing include the need for assessment of multiple variants in both DNA and RNA, sample quality and quantity, cost, and clinical need for rapid turn-around time for timely treatment initiation (recommended <14 days). Aspyre Clinical Test for Lung (Tissue or Blood) is a targeted genomic profiling assay which informs on 114 actionable and prognostic biomarkers across 11 first-line genes ( ALK , BRAF , EGFR , ERBB2 , KRAS , MET , RET , ROS1 , NTRK1 / 2 / 3 ) in patients with NSCLC. The novel assay uses standard PCR and real-time PCR equipment and interrogates nucleic acid directly without a capture step in a highly sensitive and cost-effective manner, enabling rapid and accurate clinical decision making. We present results from an initial cohort of clinical samples sent to Biofidelity Inc. Laboratory (a CAP/CLIA site). De-identified demographic and clinical data were analyzed including biopsy type, pathology diagnosis, tumor content, % necrosis, turnaround time, and variant identified. 177 clinical samples were analyzed, with retrospective, research and non-NSCLC samples excluded prior to analysis. 177 samples were eligible for inclusion. Diagnoses included adenocarcinoma (n=90), squamous cell carcinoma (n=34), unspecified NSCLC (n=49) and other (n=4). 20/177 samples were quantity not sufficient for one or more of tumor (n=11), DNA (n=6) or RNA (n=9); however, 177/177 samples passed internal assay performance checks for both DNA and RNA analysis (100%). Median tumor content was 40% (range 2-95%). Overall, 85 (47.8 %) of samples were positive for a variant, including SNV in BRAF , EGFR , and KRAS , EGFR exon 19 deletions and exon 20 insertions, insertions in ERBB2 , MET exon 14 skipping and gene fusions involving ALK , RET and ROS1 . QNS samples yielded nine variant calls of which seven were actionable. Of the samples with associated staging information, 32 were Stages I-IIIA (with 22 variant calls, 68.8%) and 30 were IIIB-IV (with 18 variant calls, 60.0%). 93.2% of samples were reported within the target two-day turnaround time (median 2, range 1-4). Aspyre Lung (Tissue) has a high assay success rate and proven rapid 2-day turnaround time, suitable as a cost-effective method for first-line or at relapse testing option, or for samples that are scant, of low quality, and can provide a large fraction of NSCLC patients with actionable biomarker information. Aspyre Lung Tissue simplified genomic profiling offers a new paradigm for informing cancer care management and enables more patients with NSCLC to benefit from effective and better tolerated targeted therapies.