Background: Colorectal cancer remains a significant source of morbidity and mortality within the United States, causing nearly 53,000 deaths in 2021. For unresectable pts, the estimated 5-year survival rate is 14%. Given recent advances in treatment, 50% of pts with mCRC will receive third-line therapy or greater, making optimization of therapy in these settings pivotal. Trifluridine-tipiracil (TAS-102) is FDA approved for third-line or greater in mCRC per the RECOURSE Trial. Standard dosing is 35 mg/m² twice daily (maximum = 80 mg/day) on Days 1-5 and Days 8-12 of 28-day cycles. This dosing schedule is associated with Grade 3-4 neutropenia (38%), requiring treatment delays (53%), dose reductions (14%) and G-CSF support (9%). To reduce this toxicity while maintaining efficacy, we studied an alternative biweekly dosing (Days 1-5 and Days 15-19 of 28-day cycles). Methods: A retrospective analysis was completed (2019-2021) at Vanderbilt-Ingram Cancer Center in pts with refractory mCRC and appendiceal cancer (CA) who completed > 12 days of TAS-102 therapy. Diagnostic imaging was completed every 8-12 weeks. Patient data was evaluated for lines of prior therapy, ECOG performance status (PS), the addition of bevacizumab, and CTCAE grade of treatment-related myelotoxicity. Evaluation of progression-free survival (PFS) was performed only in mCRC pts. Results: 24 pts met the criteria, with a mCRC:appendiceal CA ratio of 20:4 and Male:Female 13:11. Median age 61.5 yrs (range 31-80); median number of prior therapies 3; median ECOG PS of 1; and median duration of therapy 73.5 days. Hematologic toxicities: Neutropenia 30% [Grade 3 (13%), Grade 4 (0%)]; anemia 17.4% [Grade 3 (8.7%), Grade 4 (0%)]; thrombocytopenia 4.3% [Grade 3/4 (0%)]. No pts required G-CSF. One patient required a treatment-related dose delay (neutropenia), and 2 pts required dose reductions (fatigue). In mCRC pts, the median PFS was 2.3 months. To date, 7 mCRC pts remain on treatment (range: 38-385). Conclusions: In our retrospective cohort analysis, TAS-102 biweekly dosing schedule (35 mg/m² twice daily; Days 1-5 and Days 15-19 of 28-day cycles) for pts with refractory mCRC and appendiceal CA reduced Grade 3 myelotoxicity without Grade 4 toxicities, while preserving PFS in pts with mCRC. With an improved toxicity profile, this alternative TAS -102 dosing schedule may be a more favorable option for future combination studies. Additional prospective data are needed to validate these findings. To our knowledge, this is the first analysis of biweekly TAS-102 in a US patient population.