Key Inclusion Criteria: Subjects eligible for inclusion in this study have to meet all inclusion criteria for this study. Below is a list limited to the key inclusion criteria: ·ð Sign and date the Tissue Pre-Screening and Main ICFs, prior to the start of any respective study-specific qualification procedures. ·ð Adults aged e"20 years in Japan, Taiwan, and Korea, or those aged e"18 years in other countries, at the time the ICFs are signed. (Please follow local regulatory requirements if the legal age of consent for study participation is >18 years). ·ð Pathologically-documented, unresectable, recurrent, or metastatic colorectal adenocarcinoma. Subject must have BRAF wild-type cancer and RAS status identified in primary or metastatic site, tested by a Clinical Laboratory Improvement Act (CLIA), ISO15189, or equivalent-certified laboratory. ·ð The following therapies should be included in prior lines of therapy: o Fluoropyrimidine, oxaliplatin, and irinotecan, unless contraindicated o Anti-epidermal growth factor receptor (EGFR) treatment, if RAS wild-type and if clinically indicated o Anti-vascular endothelial growth factor (VEGF) treatment, if clinically indicated o Anti-programmed death-ligand 1 (PD-[L]-1) therapy, if tumor is microsatellite instable (MSI)- high/deficient mismatch repair (dMMR), or tumor mutational burden (TMB)-high, if clinically indicated ·ð Is willing and able to provide an adequate tumor sample for tissue pre-screening to confirm HER2 status by central laboratory (most recent tumor tissue preferred). ·ð Confirmed HER2-overexpressing status assessed by central laboratory and defined as IHC 3+ or IHC 2+/ISH+. ·ð Presence of at least one measurable lesion assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Lesions situated in a previously-irradiated area are considered measurable if progression has been demonstrated in such lesions after the end of radiotherapy. ·ð ECOG PS of 0 or 1. ·ð Has left ventricular ejection fraction (LVEF) e"50% within 28 days before randomization/registration. ·ð Has adequate organ function within 14 days before randomization/registration, defined as: Parameter Laboratory value Adequate bone marrow function Platelet count ³ð100,000/mm3 (Platelet transfusion is not allowed within 1 week prior to Screening assessment) Hemoglobin e"9.0 g/dL (Red blood cell transfusion is not allowed within 1 week prior to Screening assessment) Absolute neutrophil count (ANC) ³ð1500/mm3 (granulocyte-colony stimulating factor [G-CSF] administration is not allowed within 1 week prior to Screening assessment) Adequate renal function Creatinine Creatinine clearance e"30 mL/min as calculated using the Cockcroft-Gault equation Adequate hepatic function Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) d"5 ´ð upper limit of normal (ULN) Total bilirubin d"1.5 ´ð ULN if no liver metastases or <3 ´ð ULN in the presence of documented Gilbert syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline Serum Albumin e"2.5 g/dL Adequate blood clotting function International normalized ratio (INR)/Prothrombin time (PT) and either partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) d"1.5 × ULN ·ð Has adequate treatment washout period before randomization/registration, defined as: Treatment Washout Period Major surgery e"4 weeks Radiation therapy, including palliative stereotactic radiation to chest e"4 weeks (palliative stereotactic radiation therapy to other areas e"2 weeks) Anticancer chemotherapy (immunotherapy [non-antibodybased therapy]), retinoid therapy e"3 weeks (e"2 weeks or 5 half-lives, whichever is longer, for small-molecule targeted agents such as 5-fluorouracilbased agents, folinate agents, weekly paclitaxel, e"6 weeks for nitrosoureas or mitomycin C) Antibody-based anticancer therapy e"4 weeks Chloroquine/hydroxychloroquine >14 days

Subjects meeting any exclusion criteria for this study will be excluded from this study. Below is a list limited to the key exclusion criteria: " Medical history of myocardial infarction (MI) within 6 months before randomization/registration, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV). Subjects with troponin levels above ULN at Screening (as defined by the manufacturer), and without any MI-related symptoms, should have a cardiologic consultation before randomization/registration to rule out MI. " Has a corrected QT interval (QTcF) prolongation to >470 msec (female subjects) or >450 msec (male subjects) based on the average of the Screening triplicate 12-lead ECGs. " Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening. " Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the randomization/registration, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.). " Any autoimmune, connective tissue, or inflammatory disorders (eg, rheumatoid arthritis, Sjögren syndrome, sarcoidosis, etc.) where there is documented, or a suspicion of, pulmonary involvement at the time of Screening. Full details of the disorder should be recorded in the eCRF for subjects who are included in the study. " Prior pneumonectomy. " Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and randomization/registration. " Subjects with leptomeningeal carcinomatosis. " Has multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated. " Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product. " Has a history of severe hypersensitivity reactions to other monoclonal antibodies. " Has an uncontrolled infection requiring intravenous antibiotics, antivirals, or antifungals. " Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions that may in the opinion of the Investigator, interfere with the subject s participation in the clinical study or evaluation of the clinical study results. " Has known human immunodeficiency virus (HIV) infection. Unless required by local regulations or institutional review board (IRB)/ethics committee (EC), an HIV antigen/antibody test is not required prior to randomization/enrollment. " Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of viral infection within 28 days before study randomization/registration. Subjects with past or resolved hepatitis B virus (HBV) infection are eligible if hepatitis B surface antigen (HBsAg) negative (-) and antibody to hepatitis B core antigen (anti-HBc) positive (+). Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. " Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCICTCAE) version 5.0, Grade d"1 or baseline. Subjects with chronic Grade 2 toxicities may be eligible at the discretion of the Investigator and approval of the Sponsor. " Previous treatment with a DXd-containing antibody-drug conjugate (ADC). " Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection. Note: Subjects with localized fungal infections of skin or nails are eligible. " Female subject who is pregnant, breastfeeding, or intends to become pregnant during the study.