Background: Commonly used systemic therapies in metastatic colorectal cancer (CRC) for patients who have progressed through available first- and second-line regimens are regorafenib or trifluridine/tipiracil. For the subset of metastatic CRC patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusions, there are two additional approved options, larotrectinib or entrectinib. Our objective was to estimate and compare expected life-years (LYs) and quality-adjusted life-years (QALYs) for metastatic TRK fusion CRC patients receiving larotrectinib versus entrectinib. Methods: We developed a partitioned survival model to project long-term comparative effectiveness of larotrectinib vs. entrectinib. Extrapolation was necessary as follow-up for both drugs was less than three years at the time of data reporting. Survival data for larotrectininb, assessed by independent review committee, were derived from a July 2020 analysis of 8 adult (≥18 years of age) TRK fusion CRC patients from the larotrectinib clinical trials program (NCT02122913, NCT02637687, and NCT02576431). Survival inputs for entrectinib were derived from 7 TRK fusion CRC patients from an October 2018 integrated analysis of three single arm trials (EudraCT 2012-000148-88, NCT02097810, and NCT02568267). Progression-free survival (PFS) and overall survival (OS) for both treatments were estimated using parametric survival distributions (Exponential, Weibull, Log-logistic, and Log-normal) fit to the available data. Exponential curves were used based on goodness-of-fit and clinical plausibility. QALYs were estimated by adjusting the time spent in the pre-progression and post-progression health states by health state utilities derived from publicly available literature. A constant discount rate of 3% was applied to LYs and QALYs. Model uncertainty was evaluated using one-way sensitivity analysis and probabilistic sensitivity analysis with 10,000 simulations. Results: Larotrectinib resulted in 2.11 LYs and 1.60 QALYs compared to 0.53 LYs and 0.41 QALYs for entrectinib. These estimates yielded additional gains for larotrectinib of 1.58 LYs and 1.19 QALYs against entrectinib. Conclusions: In metastatic TRK fusion CRC, larotrectinib may produce substantial life expectancy and quality-adjusted life-year gains compared to entrectinib. Additional data with longer follow-up times will further inform this comparison.