Binimetinib and Palbociclib or TAS-102 in Treating Patients With KRAS and NRAS Mutant Metastatic or Unresectable Colorectal Cancer

Prior treatment with drug targeting BRAF, MEK, ERK, or CDK family

* NOTE: For the purpose of this protocol, prior treatment with regorafenib is allowed

Prior treatment with trifluridine/tipiracil (TAS-102)

Pregnant or nursing (lactating women), where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test

Women of child-bearing potential

* NOTE: defined as all women physiologically capable of becoming pregnant, unless they agree to use highly effective methods of contraception throughout the study and for 8 weeks after study drug discontinuation

* NOTE: Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation \>= 42 days prior to registration/randomization. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential

Sexually active males

* NOTE: unless they agree to use highly effective methods of contraception throughout the study and for 12 weeks after study drug discontinuation and should not father a child in this period

Any symptomatic brain metastasis

* NOTE: Patients previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable for \>= 4 weeks prior to registration/randomization, with imaging (e.g., magnetic resonance imaging \[MRI\] or computed tomography \[CT\]) demonstrating no current evidence of progressive brain metastases at registration/randomization

Prior treatment =\< 21 days prior to registration/randomization with any other chemotherapy, small molecule inhibitor (e.g. regorafenib), monoclonal antibody, immunotherapy, or radiotherapy

* NOTE: All toxicities from prior therapy must be =\< grade 1 (or =\< grade 2 for peripheral neuropathy or alopecia)

Impaired cardiovascular function or clinically significant cardiac diseases, including any of the following:

* History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) \< 6 months prior to registration/randomization

* Symptomatic chronic heart failure (i.e. grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality \< 6 months prior to registration/randomization except atrial fibrillation and paroxysmal supraventricular tachycardia

* Left ventricular ejection fraction (LVEF) \< 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram =\< 28 days prior to registration/randomization

Uncontrolled hypertension, defined as persistent elevation of systolic blood pressure \>= 150 mmHg or diastolic blood pressure \>= 100mmHg despite current therapy

History of thromboembolic or cerebrovascular events =\< 12 weeks prior registration/randomization. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e. massive or submassive) deep vein thrombosis or pulmonary emboli

* Note: Patients with either deep vein thrombosis or pulmonary emboli that does not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants for at least 4 weeks

* Note: Patients with thromboembolic events related to indwelling catheters or other procedures may be enrolled

Known history of acute or chronic pancreatitis =\< 6 months prior to registration/randomization

Known positive serology for HIV (human immunodeficiency virus), active hepatitis B, and/or active hepatitis C infection

Patients who have neuromuscular disorders that are associated with elevated creatine phosphokinase (CPK) (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)

History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) =\< 12 months prior to registration/randomization

Impaired gastrointestinal (GI) function or disease that may significantly alter the absorption of binimetinib or palbociclib (e.g., ulcerative disease, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption) in the opinion of the investigator

History or current evidence of retinal vein occlusion (RVO) or current risk factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)

Leptomeningeal disease

Known hypersensitivity to the components of study drugs or its analogs

Known medical, psychiatric, substance abuse, or cognitive disorder that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements in the opinion of the investigator

Patients who have undergone major surgery =\< 21 days prior to registration/randomization or who have not recovered from side effects of such procedures

Any other co-morbid, systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

Previous or concurrent malignancy =\< 3 years prior to registration/randomization with the following exceptions:

* Adequately treated basal cell or squamous cell carcinoma of the skin

* Superficial bladder cancer

* Prostate intraepithelial neoplasm

* In situ carcinoma of the cervix

* Other solid tumors treated curatively without evidence of recurrence for \>= 3 years prior to registration/randomization

* NOTE: If there is a history or prior malignancy, must not be receiving other specific anti-cancer treatment such as anti-estrogen, anti-androgen, or other tyrosine kinase inhibitor therapy

* NOTE: For the purpose of this protocol, prior treatment with regorafenib is allowed

* NOTE: Defined as all women physiologically capable of becoming pregnant, unless they agree to use highly effective methods of contraception throughout the study and for 8 weeks after study drug discontinuation

* NOTE: Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation \>= 42 days of re-registration. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential

* NOTE: unless they agree to use highly effective methods of contraception throughout the study and for 12 weeks after study drug discontinuation and should not father a child in this period

* NOTE: Patients previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable for \>= 4 weeks, with imaging (e.g., MRI or CT) demonstrating no current evidence of progressive brain metastases at re-registration

* History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) \< 6 months prior to re-registration

* Symptomatic chronic heart failure (i.e., grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality \< 6 months prior to re-registration except atrial fibrillation and paroxysmal supraventricular tachycardia

* Left ventricular ejection fraction (LVEF) \< 50% as determined by a MUGA scan or echocardiogram

* Note: Patients with either deep vein thrombosis or pulmonary emboli that does not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants for at least 4 weeks

* Note: Patients with thromboembolic events relat

What this study is about