Tucatinib with Trastuzumab and mFOLFOX6 for HER2+ Colorectal Cancer

Inclusion Criteria: * Histologically and/or cytologically confirmed adenocarcinoma of the colon or rectum which is locally advanced unresectable or metastatic * Able to provide the most recently available formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks (or freshly sectioned slides) obtained prior to treatment initiation to a central laboratory * If archival tissue is not available, a newly-obtained baseline biopsy of an accessible tumor lesion is required within 35 days prior to start of study treatment * HER2+ disease as determined by a tissue based assay performed at a central laboratory. * Participant has rat sarcoma viral oncogene homolog wild-type (RAS WT) disease as determined by local or central testing. For central RAS analysis, tissue sample must be analyzed within 1 year of biopsy date. * Radiographically measurable disease per RECIST v1.1 with: * At least one site of disease that is measurable and that has not been previously irradiated, or * If the participant has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * CNS Inclusion - based on contrast brain magnetic resonance imaging, participants may have any of the following: * No evidence of brain metastases * Previously treated brain metastases which are asymptomatic Exclusion Criteria: * Prior systemic anticancer therapy for colorectal cancer (CRC) in the locally advanced unresectable or metastatic setting; note that participants may have received a maximum of 2 doses of mFOLFOX6 in the locally advanced/unresectable or metastatic setting prior to randomization. * Note: May have received chemotherapy for CRC in the adjuvant setting if it was completed \>6 months prior to enrollment * Radiation therapy within 14 days prior to enrollment (or within 7 days in the setting of stereotactic radiosurgery) * Previous treatment with anti-HER2 therapy * Ongoing Grade 3 or higher neuropathy * Active or untreated gastrointestinal (GI) perforation at the time of screening.