Trametinib and Trifluridine and Tipiracil Hydrochloride in Treating Patients With Colon or Rectal Cancer That is Advanced, Metastatic, or Cannot Be Removed by Surgery

Inclusion Criteria: * All subjects must have the ability to understand and the willingness to sign a written informed consent * All patients must be able to take oral medications * All patients must be deemed by investigator to have the initiative and means to be compliant with the study protocol (treatment and follow-up) * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 * Pathologically confirmed advanced, unresectable, or metastatic colon or rectal cancer who have had intolerance to or progression after a fluoropyrimidine, oxaliplatin, irinotecan, and cetuximab or panitumumab in the event of wild-type RAS/BRAF tumors * Of note, prior bevacizumab or regorafenib exposure is not mandated as some patients are deemed poor candidates for anti-angiogenesis therapy and never receive these agents * Tumors must have undergone expanded molecular profiling with a Clinical Laboratory Improvement Act (CLIA)-certified platform that evaluates, at a minimum, RAS, PIK3CA, PTEN and BRAF mutations status * Documented RAS-mutated tumor without activating PIK3CA mutations or PTEN mutation (loss of PTEN or silencing) * Measurable disease by RECIST 1.1 guidelines * Last chemotherapy at least 3 weeks from initiation of study treatment * No investigational agents within 4 weeks from initiation of study treatment * Negative serum or urine beta-human chorionic gonadotropin (HcG) test (female patient of childbearing potential only) performed within 72 hours of prior to first stud…