Sym004 Versus Futuximab or Modotuximab in Patients With mCRC

Inclusion Criteria: * Male or female patients, ≥ 18 years of age at the time of obtaining informed consent. * Histologically- or cytologically-confirmed mCRC. * Microsatellite instability-high (MSI-H) / mismatch repair-deficient (dMMR) tumors must have received prior therapy with pembrolizumab, nivolumab, or other programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway blocker, and must have progressed on that therapy. * Meeting the protocol definition of TNmCRC assessed in the screening blood test. * mCRC currently not amenable to surgical intervention due to either medical contraindications or non-resectability of the tumor. * Measurable disease according to RECIST v1.1, and willingness to undergo a total of 2 biopsies of a primary or metastatic tumor site(s) considered safely accessible for biopsy. * Must have received at least 2 prior regimens of standard chemotherapy for mCRC and must have been refractory to or failed (includes intolerance to) those regimens. Prior standard chemotherapy may not have included TAS-102 or regorafenib, but must have included agents as specified in the protocol. * "Acquired" resistance to commercially available anti-EGFR mAbs approved for the treatment of mCRC must have: 1. Received treatment with an anti-EGFR for ≥16 weeks 2. Progressive disease (PD) documented by imaging or clinical findings less than or equal to 6 calendar months after cessation of previous anti-EGFR mAb treatment 3. No more than 6 calendar months from last dose of previous anti-EGFR mAb treatment to date of consent for this trial (regardless of the line of therapy in which it was used) * Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 * Not of childbearing potential or who agree to use a highly effective method of contraception during the study beginning within 2 weeks prior to the first dose and continuing until 3 months after the last dose of study drug. Exclusion Criteria: * Women who are pregnant or lactating or intending to become pregnant before, during, or within 3 months after the last dose of study drug. * Prior history of specific mutations (specified in the protocol) in the tumor 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 the last 5 years, with exceptions. * Active thrombosis, or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE) within 4 weeks prior to first administration of study drug 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 \> Grade 1 from prior anti-EGFR therapy at the time of randomization. * Unresolved \> Grade 1 toxicity associated with any prior antineoplastic therapy Drugs and Other Treatments Exclusion Criteria: * Prior treatment with TAS-102 or regorafenib * Any antineoplastic agent for the primary malignancy (standard or investigational) without delayed toxicity within 4 weeks prior to first administration of IMP and during study with exceptions * Any other investigational treatments within 4 weeks prior to and during study; includes participation in any medical device or other therapeutic intervention clinical trials * Radiotherapy as specified in the protocol * Immunosuppressive or systemic hormonal therapy (\> 10 mg daily prednisone equivalent) within 2 weeks prior to first administration of IMP and during study; allowed therapies are specified in the protocol.