• 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