Background: Metastatic non-small cell lung cancer (mNSCLC) patients (pts) should be tested for genomic alterations (GA) to inform treatment decisions. This study assesses the economic impact of next generation sequencing (NGS) vs sequential single-gene testing modalities for Center for Medicare and Medicaid Services (CMS) Medicare and US commercial payers. Methods: In a decision analytic model, newly diagnosed mNSCLC pts were modeled to receive PD-L1 and GA tests (EGFR, ALK, ROS1, BRAF, MET, HER2, RET, NTRK1) using 1) sequential tests, 2) exclusionary mutation (KRAS) test followed by sequential tests 3) panel test or 4) upfront NGS, including all GAs and KRAS. Pts in modalities 1-3 were tested for GAs with currently approved treatment (EGFR, ALK, ROS1, BRAF) followed by single-gene tests or NGS for other GAs (e.g., HER2); a proportion were assumed to need rebiopsy. Inputs included turnaround time, unit costs and mNSCLC prevalence based on literature, public data and expert opinion. Time to receive results and total cost (test + rebiopsy) were calculated for each modality and compared with NGS. Results: For hypothetical 1 million-member plans, an estimated 2,066 CMS Medicare and 156 commercially insured mNSCLC pts would be tested for GA. Estimated time to receive results was 2.0 weeks for NGS and panel, 2.7 and 2.8 weeks faster than exclusionary and sequential, respectively. Using CMS reimbursement, NGS represented savings of $1,393,678 vs exclusionary, $1,530,869 vs sequential and $2,140,795 vs panel. For commercial payers, NGS remained the least expensive by $3,809 (vs exclusionary) to $250,842 (vs panel). Conclusions: Our model estimated that upfront NGS leads to the same (as panel) or shorter (vs exclusionary and sequential testing) wait time for results and the lowest payer cost to establish GA status for newly diagnosed mNSCLC pts to inform treatment decisions.