Tucatinib Combined with Trastuzumab and TAS-102 for the Treatment of HER2 Positive Metastatic Colorectal Cancer in Molecularly Selected Patients, 3T Study

Registered to COLOMATE ACCRU-GI-1611 and:

* COLOMATE Companion Trial Recommendation Form indicates patient meets molecular eligibility for enrollment to this study (at least one of the following: PIK3CA, KRAS, NRAS, or BRAF V600 mutation detected in blood from the Guardant360 assay)

* COLOMATE Companion Trial Recommendation Form date of completion is \< 90 days prior to registration

Age \>= 18 years

Histologically and/or cytologically confirmed metastatic adenocarcinoma of the colon or rectum

Life expectancy \>= 3 months in the estimation of the investigator

Previous treatment with or contraindication to:

* A fluoropyrimidine (e.g., 5-fluorouracil or capecitabine)

* Oxaliplatin

* Irinotecan

* An anti-VEGF biological therapy (including but not limited to bevacizumab, ramucirumab, or ziv-aflibercept)

* If the tumor has deficient mismatch repair proteins or is microsatellite instability (MSI)-High based on tumor tissue testing, an anti-PD-1 monoclonal antibody (nivolumab or pembrolizumab)

* (Cancer Therapy List \[colorectal cancer\] is available on the Academic and Community Cancer Research United \[ACCRU\] web site)

Radiographically measurable disease as per Response Evaulation Criteria in Solid Tumors (RECIST) version 1.1

Molecular testing result from Clinical Laboratory Improvement Act (CLIA)-certified laboratory confirming that the tumor tissue has at least one of the following:

* HER2 3+ by immunohistochemistry (IHC)

* HER2 2+ by IHC and HER2 (ERBB2) amplification by in situ hybridization assay (Signal ratio \> 2.2 or gene copy number \> 6 by either fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH)

* HER2 (ERBB2) amplification by CLIA-certified next generation sequencing (NGS) assay

Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1, or 2 (Form is available on the ACCRU web site)

Absolute neutrophil count (ANC) \>= 1500/mm\^3 (obtained =\< 7 days prior to registration)

Platelet count \>= 100,000/mm\^3 (obtained =\< 7 days prior to registration)

Hemoglobin \> 8.0 g/dL (obtained =\< 7 days prior to registration)

Total bilirubin =\< 1.5 x upper limit of normal (ULN) (obtained =\< 7 days prior to registration)

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =\< 3 X upper limit of normal (ULN) (obtained =\< 7 days prior to registration)

Creatinine clearance (using Cockcroft and Gault equation) \>= 50 mL/min or serum creatinine less than 1.5 x the upper limit of institutional normal (ULN) (obtained =\< 7 days prior to registration)

International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =\< 1.5 X ULN unless on medication known to alter INR and/or aPTT (obtained =\< 7 days prior to registration)

Negative serum pregnancy test =\< 7 days prior to registration for women of childbearing potential only. Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post menopause is defined as amenorrhea \>= 12 consecutive months Note: Women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression or any other reversible treatment

Sexually active subjects (men and women) agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used

Willing to provide informed written consent =\< 30 days prior to registration

Left ventricular ejection fraction (LVEF) \>= 50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented =\< 28 days prior to registration

Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

* Note: During the Active Monitoring Phase of a study (i.e., active treatment and clinical follow-up), participants must be willing to return to the consenting institution for follow-up

Willing to provide tissue and blood samples for correlative research purposes

Willing to allow transfer of tissue and blood samples, clinical information, and outcome data collected from this trial for future research

Tucatinib Combined with Trastuzumab and TAS-102 for the Treatment of HER2 Positive Metastatic Colorectal Cancer in Molecularly Selected Patients, 3T Study

What this study is about

Tucatinib Combined with Trastuzumab and TAS-102 for the Treatment of HER2 Positive Metastatic Colorectal Cancer in Molecularly Selected Patients, 3T Study

What this study is about