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 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
• GI perforation within 12 months of enrollment

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 07/03/2024. Questions regarding updates should be directed to the study team contact.