Upfront Trastuzumab-Deruxtecan Plus Capecitabine and Bevacizumab for Patients With HER-2 Positive Metastatic Colorectal Cancer.

Inclusion Criteria: * Written informed consent obtained from the patient/legal representative before performing any protocol-related procedures, including screening evaluations. * Patient state to comply with all the study procedures and treatments. Patients must be accessible for treatment and follow-up. Patients registered for this trial must be treated and followed at the participating Centre. * Age ≥ 18 years at the time of informed consent. * ECOG Performance Status ≤ 2. * Life expectancy of ≥ 3 months. * Have histologically documented adenocarcinoma of the colon or rectum, which is initially metastatic or unresectable locally advanced. * Subjects must be willing to provide the most recently available formalin-fixed paraffin-embedded tumor tissue blocks (or at least 25 freshly sectioned slides) for translational analyses (sampled before 1st treatment course). If archival tissue is not available for HER2 testing or for exploratory aims, then a newly obtained baseline biopsy of an accessible tumor lesion is required before Cycle 1 Day 1 timeframe. Biopsy must contain adequate tissue for analysis; the following biopsy types are acceptable: resection, excision, punch (skin lesions only) and core needle biopsies. * Presence of locally determined HER2 overexpression/amplification defined as IHC 3+ or 2+/ISH amplified on archival/newly obtained tumor tissue, according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for gastric/gastroesophageal cancer. * Have RAS known status and pMMR/MSS status by standard local testing. * Have radiographically measurable disease per RECIST v1.1. * Have adequate hematological, hepatic, renal, cardiac and coagulation function, as defined below, obtained ≤ 7 days prior to enrollment (Cycle 1 Day 1): * Absolute neutrophil count (ANC) ≥ 1500/mm3. (Granulocyte-colony stimulating factor administration is not allowed within 1 week prior to C1D1). * Platelet count ≥ 100000/mm3. (Platelet transfusion is not allowed within 1 week prior to C1D1) * Hemoglobin ≥ 9.0 g/dL * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline. * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN (≤ 5 x ULN if liver metastases are present). * Serum albumin ≥ 2.5 g/dL. * Creatinine clearance ≥ 60 mL/min as determined by Cockcroft-Gault (using actual body weight). * Left ventricular ejection fraction (LVEF) ≥ 50% within 28 days before enrollment. * International normalized ratio or Prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 x ULN. * Have had adequate washout period from previous treatment before screening, defined as: * ≥ 4 weeks from major surgery. * ≥ 4 weeks from radiation therapy, including palliative stereotactic radiation therapy to the chest. * ≥ 3 weeks from anti-cancer chemotherapy \[immunotherapy (non-antibody-based therapy)\], retinoid therapy, hormonal therapy. * ≥ 4 weeks from antibody-based anti-cancer therapy * ≥ 2 weeks or 5 half-lives (whichever is longer) from targeted agent- and small molecule-based therapy * ≥ 6 weeks from nitrosureas or mitomycin C * ≥ 1 week from TKIs approved for treatment of patients with non-small-cell lung cancer (baseline CT must be completed after discontinuation of TKI) * \> 2 weeks from chloroquine/hydroxychloroquine * ≥ 2 weeks from cell-free and Concentrated Ascites Reinfusion Therapy (CART), peritoneal shunt or drainage of ascites, pleural or pericardial effusion. * Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta- human chorionic gonadotropin (β-HCG) pregnancy test prior to each administration of IP. Women of childbearing potential are defined as those who are not surgically sterile (i.e. underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. * Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, presented in Table 1. From the time of screening and must agree to continue using such precautions for 7 months after the last dose of investigational product (IP). Not all methods of contraception are highly effective. Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of IP. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is line with the patient's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic, or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. * Female participants must not donate, or retrieve for their own use, ova from the time of enrolment and throughout the study treatment period, and for at least 7 months after the final study drug administration. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrollment in this study. * Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of IP for T-DXd while 6 months for capecitabine and bevacizumab. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive me