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

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 study dose

Absolute neutrophil count (ANC) \>= 1500/mm\^3 (to be performed within 28 days prior to day 1 of protocol therapy)

* NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement

Platelets \>= 75,000/mm\^3 without transfusions (to be performed within 28 days prior to day 1 of protocol therapy)

Hemoglobin (Hgb) \>= 8 g/dL without transfusions (to be performed within 28 days prior to day 1 of protocol therapy)

Total serum bilirubin \< upper limit of normal (ULN) (to be performed within 28 days prior to day 1 of protocol therapy)

Aspartate aminotransferase (AST) =\< 2.5 x ULN if no liver metastases or =\< 5 x ULN if liver metastases (to be performed within 28 days prior to day 1 of protocol therapy)

Alanine aminotransferase (ALT) =\< 2.5 x ULN if no liver metastases or =\< 5 x ULN if liver metastases (to be performed within 28 days prior to day 1 of protocol therapy)

Creatinine \< 1.5 x ULN or creatinine clearance of \>= 60 mL/min per the Cockcroft-Gault formula (to be performed within 28 days prior to day 1 of protocol therapy)

Female of childbearing potential: negative urine or serum pregnancy test (to be performed within 28 days prior to day 1 of protocol therapy)

* If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

Corrected QT (QTc) interval =\< 480 ms (12 lead-electrocardiography \[ECG\]) (to be performed within 28 days prior to day 1 of protocol therapy)

Left ventricular ejection fraction \>= 50% as determined by multigated acquisition (MUGA) scan or echocardiogram (to be performed within 28 days prior to day 1 of protocol therapy)

Normal eye examination (to be performed within 28 days prior to day 1 of protocol therapy)

Women of childbearing potential must use highly effective methods of contraception throughout the study and for 4 months after study drug discontinuation

Sexually active men must use a condom during intercourse while taking study drug and for 60 days after study drug discontinuation; a condom is required for vasectomized men to prevent delivery of study drug via seminal fluid

What this study is about