A Study of Tucatinib With Trastuzumab and mFOLFOX6 Versus Standard of Care Treatment in First-line HER2+ Metastatic Colorectal Cancer

Inclusion Criteria:

• Histologically and/or cytologically confirmed adenocarcinoma of the colon or rectumwhich 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 treatmentinitiation to a central laboratory

• If archival tissue is not available, a newly-obtained baseline biopsy of anaccessible tumor lesion is required within 35 days prior to start of studytreatment

• HER2+ disease as determined by a tissue based assay performed at a centrallaboratory.

• Participant has rat sarcoma viral oncogene homolog wild-type (RAS WT) disease asdetermined by local or central testing. For central RAS analysis, tissue sample mustbe 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 beenpreviously irradiated, or

• If the participant has had previous radiation to the target lesion(s), theremust 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 mayhave 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 locallyadvanced unresectable or metastatic setting; note that participants may havereceived a maximum of 2 doses of mFOLFOX6 in the locally advanced/unresectable ormetastatic setting prior to randomization.

• Note: May have received chemotherapy for CRC in the adjuvant setting if it wascompleted >6 months prior to enrollment

• Radiation therapy within 14 days prior to enrollment (or within 7 days in thesetting 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.