Background: Cemiplimab monotherapy (mono) demonstrated significant survival benefit versus chemotherapy (CT) in the first-line (1L) treatment of advanced NSCLC with PD-L1 ≥50%. This analysis estimated the BI of introducing cemiplimab in the US from the healthcare payer’s perspective, in the context of available treatments. Methods: Cohorts of patients (pts) with advanced NSCLC and PD-L1 ≥50% without EGFR/ALK mutations were modeled over 3 years (yrs). Treatment duration inputs were based on median progression-free survival (PFS) from EMPOWER-Lung 1 trial for cemiplimab and CT, and published data on median PFS for other immuno-oncology (IO) agents. Market shares were based on market research and assumed the following distribution in the scenario without cemiplimab: 68% pembrolizumab (pembro); 15% pembro + CT; 6% durvalumab (durva); 4% platinum CT; 3% atezolizumab (atezo); 2% nivolumab (nivo); and 2% nivo + ipilimumab (ipi). Cemiplimab market share was assumed to increase from 1% (yr 1), to 6% (yr 2), to 10% (yr 3). The analysis assumed that 50% of the cemiplimab market share will come from displacement of pembro mono, whilst the other 50% will come from displacement of platinum CT, atezo, durva, nivo, and nivo + ipi. The market share for pembro + CT was assumed to remain the same in both scenarios. Monthly list price of cemiplimab was lower than pembro and nivo at the time of this research and were sourced from ProspectoRx drug pricing database. Adverse event costs were estimated using HCUP 2017 data and ICD-10 codes specific to each event and inflated to 2019 costs using medical inflation indices from Bureau of Labour Statistics. Disease management costs were per Centers for Medicare and Medicaid Services data. In univariate sensitivity analyses, inputs were varied by ±20% to model the impact on total incremental costs over 3 yrs. Results: In a hypothetical US healthcare plan of 1,000,000 members, ̃60 were eligible to receive 1L cemiplimab treatment for advanced NSCLC with PD-L1 ≥50% in yr 1. The average incremental cost per member per month was $0.0038. The 3-yr incremental cumulative BI of cemiplimab was $138,463, representing a 0.561% increase in the healthcare payer’s 3-yr expenditures on these 60 pts. The incremental cost of adding cemiplimab was $8,744 in yr 1; $50,187 in yr 2; and $79,533 in yr 3. The analysis was most sensitive to changes to the treatment duration for cemiplimab (±172%) and pembro (±93%). Changes to all other inputs had < 20% impact. Conclusions: Cemiplimab is likely to be associated with a minimal increase in the budget for 1L treatment of advanced NSCLC with PD-L1 ≥50%. With a numerically lower list price relative to pembro and nivo, BI of cemiplimab was driven by the treatment duration for cemiplimab, which was higher than comparator treatments due to increased PFS.