Background: With advances in the management of mCRC, survival outcomes of patients have improved. While some patients still progress after first and second lines of treatment, there remain options for third or later-line treatment. This study aimed to determine the cost-effectiveness of later-line (>3) treatments for patients with mCRC in the US, based on a NMA of survival curves. Unlike conventional NMA using constant hazard ratios, this method is not constrained by the proportional hazard assumption and uses parametric fitting that incorporates the shape and scale parameters to provide time-varying treatment effects. Methods: The NMA compared the efficacy of 6 treatments, atezolizumab+/-cobimetinib (ATE+/-COB), fruquintinib (FRU), regorafenib (REG), TAS-102+/-bevacizumab (TAS+/-BEV), including biosimilar, to placebo (PBO). The study used a 3-state partitioned survival model over a 5-year time horizon incorporating drug acquisition, administration, adverse events, monitoring, and end of life costs, and utilities sourced from literature. Total costs, life-years (LY) and quality-adjusted LYs (QALY) for each treatment were determined. Incremental cost-effectiveness (ICER) and incremental cost-utility ratios (ICUR) were estimated using PBO as a common comparator. Results: Over the 5-year period and across the 6 therapies, survival ranged from 0.62 LYs for PBO to 1.15 LYs for TAS+BEV, translating to QALYs ranging from 0.44 for PBO to 0.85 for TAS+BEV. Total costs of treatment ranged from 278,877 for PBO to 417,495 for TAS+BEV (405,002 with biosimilar). TAS+BEV yielded the lowest ICER of an additional 261,421 (237,860 with biosimilar)/LY gained (g) and ICUR of an additional 343,458 (312,504 with biosimilar)/QALYg; while ATE presented the least favorable ICER and ICUR of an additional $522,602/LYg and $701,381/QALYg, respectively (Table). Conclusions: Among the 6 treatments evaluated, TAS+BEV emerged as the most cost-effective later-line treatment for mCRC while atezolizumab was the least cost-effective. Additionally, replacing BEV with a biosimilar reduces costs and enhances cost-effectiveness, improving access for patients.