Background: Testing for an increasing number of biomarkers has become essential to the care of lung ADC patients (pts). This commonly requires multiple technologies and often is limited by inadequate tissue. Hybrid capture-based targeted NGS has the ability to identify relevant GAs in a single test. We undertook this study to estimate the frequency of GAs in “pan-negative” lung ADC pts with NS/LS history. Methods: Eligible pts had ≤15 pack-year smoking history (high likelihood of undetected GA) and advanced lung ADC that were “pan-negative” for mutations (EGFR, ERBB2, KRAS, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1 by hotspot testing and/or multiplex sizing assays) and fusions (ALK, ROS1, and RET by break apart FISH). Tumor required contained ≥20% tumor nuclei on FFPE material yielding ≥50 ng of DNA. NGS was performed by hybridization capture of coding exons in 287 cancer-related genes and 47 introns in 19 frequently rearranged genes (Foundation Medicine). Results: 34 pts were eligible. Previous testing required additional biopsies in 71% (n=24/34). Tissue exhaustion precluded testing in 9 of 34 pts (26%) and NGS was successfully performed in 25 pts. NGS uncovered ≥1 GA in 92% (n=23/25) of cases [median 3; 42% base substitution, 35% amplification (amp), 10% fusions, 9% in/del, 4% homozygous loss]. NGS uncovered an actionable GA with a targeted agent based on NCCN guidelines in 36% (n=9/25: EGFR G719A, EGFR L747P, ERBB2 exon 20 ins, BRAF V600E, SOCS5-ALK, CD74-ROS1, KIF5B-RET, CCDC6-RET, MET amp), and a targeted agent available on a clinical trial in 32% (n=8/25: 2 EGFR exon 18 del, FGFR1 T141R, KRAS Q61H, BRCA1 E1011K, MDM2 amp, CDK4 amp, CDKN2A loss) of pts. A GA not previously detected in lung ADCs (SHC2-ERBB2) was found in 1 pt. Reasons why non-NGS testing had not detected these GAs include lower sensitivity, test failure, use of different biopsies, technical issues, and complex or intrachromosomal rearrangements undetectable by FISH. Conclusions: NGS identified actionable GAs in 68% of NS/LS pts with “pan-negative” lung ADCs. This suggests that initial profiling of lung ADCs using NGS may be a more efficient and sensitive strategy.