Background: Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in the US, driven primarily by those with metastatic disease. For patients with metastatic disease who have progressed through available first- and second-line options, the standard of care systemic therapies are regorafenib or trifluridine/tipiracil. Larotrectinib is approved for patients with TRK fusion advanced solid tumors including metastatic CRC. Our objective was to compare expected life-years (LYs) and quality-adjusted life-years (QALYs) for metastatic CRC patients eligible to receive larotrectinib, regorafenib or trifluridine/tipiracil. Methods: We developed a partitioned survival model to project long-term comparative effectiveness of larotrectinib vs. regorafenib or trifluridine/tipiracil. Larotrectinib survival data, assessed by independent review committee, were derived from a July 2020 analysis of 8 adult (≥18 years of age) metastatic TRK fusion CRC patients from the larotrectinib clinical trials program (NCT02122913, NCT02637687, and NCT02576431). Survival inputs for regorafenib and trifluridine/tipiracil were derived from the CORRECT trial (NCT01103323) and the RECOURSE trial (NCT01607957), respectively. Progression-free (PFS) and overall survival (OS) for larotrectinib, regorafenib, and trifluridine/tipiracil were estimated using survival distributions (Exponential, Weibull, Log-logistic, and Log-normal) fit to the available data. Exponential fits 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. In accordance with standard practice in health economics and outcomes research on future health benefits, a constant discount rate of 3% was applied to the 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 0.83 LYs and 0.59 QALYs for regorafenib and 0.85 LYs and 0.60 QALYs for trifluridine/tipiracil. These estimates yielded additional gains for larotrectinib of 1.28 LYs (1.01 QALYs) and 1.26 LYs (0.99 QALYs) against regorafenib and trifluridine/tipiracil, respectively. Conclusions: In metastatic CRC, larotrectinib may produce substantial life expectancy and quality-adjusted life-year gains compared to regorafenib or trifluridine/tipiracil. Additional data with longer follow-up times will further inform this comparison.