Sym004 Versus TAS-102 in Patients With mCRC

Inclusion Criteria: * Male or female patients, ≥ 18 years of age (≥ 20 years of age in Japan) at the time of obtaining informed consent. * Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (or equivalent Karnofsky PS of 70% to 100%). * Histologically or cytologically confirmed adenocarcinoma of the colon or rectum that is metastatic. * Meeting the protocol definition of DNmCRC as assessed in the screening blood test. * mCRC not amenable to surgical intervention due to either medical contraindications or non-resectability of the tumor. * Measurable or non-measurable disease according to the Response Evaluation Criteria in Solid Tumors (Version 1.1) (RECIST v1.1). * Must have received ≥ 2 prior regimens of standard therapy for mCRC, or 1 prior regimen of standard adjuvant therapy and ≥ 1 prior regimen of standard therapy for mCRC, with failure of those regimens (due to refractory, relapsed, or progressive disease \[PD\], or due to intolerance warranting discontinuation and precluding retreatment with the same agent prior to PD). If one of the regimens utilized for inclusion is adjuvant therapy, the patient must have experienced documented recurrence by imaging studies within ≤ 6 months of completion of that therapy. Prior standard chemotherapy must have included agents as specified in the protocol (where approved in the country). * Persons of childbearing potential agreeing to use a highly effective method of contraception during the study, beginning within 2 weeks prior to the first dose of protocol therapy and continuing until 3 months after the last dose of Sym004 or 6 months after the last dose of TAS-102; male patients must also agree to refrain from sperm donation during these periods. Exclusion Criteria: * Women who are pregnant or intending to become pregnant before, during, or within 3 months after the last dose of Sym004 or 6 months after the last dose of TAS-102; women who are breastfeeding. * Prior history of specific mutations (specified in the protocol) in the tumor tissue at the time of any previous assessment. * Known, untreated central nervous system (CNS) or leptomeningeal metastases, or spinal cord compression; patients with any of these not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required. * An active second malignancy or history of another malignancy within 5 years prior to randomization, with exceptions. * Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks prior to randomization, unless adequately treated and considered by the Investigator to be stable. * Active uncontrolled bleeding or a known bleeding diathesis. * Known clinically significant cardiovascular disease or condition. * Non-healing wounds on any part of the body. * Significant gastrointestinal abnormality. * Skin rash of Grade \> 1 from prior anti-EGFR or other therapy at the time of randomization. * Any other unresolved Grade \> 1 toxicity associated with prior antineoplastic therapy, with exceptions. * Known or suspected hypersensitivity to any of the excipients of formulated Sym004 or TAS-102. Drugs and Other Treatments Exclusion Criteria: * Prior treatment with either TAS-102 or regorafenib. * Antineoplastic agents for the primary malignancy (standard or investigational) within 3 weeks prior to randomization and during study; includes chemotherapy, immunotherapy, or other biological therapy. * Other investigational treatments within 3 weeks prior to randomization and during study; includes participation in medical device or other therapeutic intervention clinical trial. * Radiotherapy within 3 weeks prior to randomization. * Immunosuppressive or glucocorticoid therapy (\> 10 mg daily prednisone or equivalent), within 2 weeks prior to randomization and during study; includes systemic or enteric corticosteroids. * Prophylactic use of hematopoietic growth factors within 1 week prior to randomization and during Cycle 1 of study; thereafter prophylactic use of growth factors is allowed as clinically indicated.