Trastuzumab Rezetecan + Bevacizumab vs. TAS-102 + Bevacizumab in Pretreated mCRC With HER2 Low/Moderate Expression or HER2 Positivity With RAS/BRAF Mutation

Inclusion Criteria

• Age ≥ 18 years; male or female.
• Histologically or cytologically confirmed unresectable locally advanced or metastatic colorectal cancer.
• Failure of prior therapy with fluoropyrimidines (e.g., 5-FU, capecitabine), oxaliplatin and irinotecan; participants with dMMR/MSI-H tumors must also have failed prior anti-PD-1/PD-L1 antibody therapy. Treatment failure is defined as:a) Disease progression (including metastasis or recurrence) during treatment;b) Disease progression within 6 months after the last dose of neoadjuvant or adjuvant therapy (including maintenance therapy);c) Permanent discontinuation of a fluoropyrimidine, oxaliplatin or irinotecan due to unacceptable non-hematologic toxicity or severe hypersensitivity, such that, in the investigator's judgment, the drug cannot be re-administered.
• Able to provide a tumor tissue sample for HER2 expression testing;
• HER2 low-to-moderate expression (IHC 2+ and FISH-negative, or IHC 1+), or HER2 positive (IHC 3+, or IHC 2+ and FISH-positive) with a RAS or BRAF mutation.
• At least one measurable lesion according to RECIST v1.1; the measurable lesion must not have received prior radiotherapy or other local therapy (a lesion located within a previously irradiated field may be selected as a target lesion if progression has been documented).
• ECOG performance status of 0-1.
• Life expectancy ≥ 12 weeks.
• Adequate major organ function as specified below (no administration of any blood products or cell growth factors is permitted within 14 days prior to screening laboratory tests):1) Adequate bone marrow reserve: absolute neutrophil count ≥ 1.5 × 10^9/L, platelets ≥ 100 × 10^9/L, hemoglobin ≥ 9 g/dL;2) Hepatic: serum albumin ≥ 3.0 g/dL, total bilirubin ≤ 1.5 × ULN, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; in the presence of liver metastases, ALT and/or AST ≤ 5 × ULN;3) Renal: serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min (Cockcroft-Gault); if urinalysis shows urine protein ≥ ++, 24-hour urine protein must be documented as ≤ 1.0 g;4) Coagulation: activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5 × ULN (participants receiving a stable dose of anticoagulant therapy, such as low-molecular-weight heparin or warfarin, with INR within the intended therapeutic range of the anticoagulant may be screened).
• Fertile participants (male and female) must agree to use a highly effective method of contraception with their partner during the study and for at least 7 months after the last dose of study drug; women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first administration of study drug.
• Voluntary participation in this study, signed informed consent, good compliance, and willingness to cooperate with follow-up.

Exclusion Criteria

• Prior receipt of any of the following:1) Prior receipt of an anti-HER2 antibody-drug conjugate containing exatecan or an exatecan derivative as a topoisomerase I inhibitor, e.g., Enhertu (DS-8201a; trastuzumab deruxtecan); 2) Receipt of the last dose of anticancer therapy within 4 weeks before the first dose of study drug, including chemotherapy, radiotherapy, biotherapy, targeted therapy or immunotherapy; Chinese herbal medicine with anticancer indications within 2 weeks before the first dose of study drug; 3) Receipt of any unapproved investigational drug or treatment within 4 weeks before the first dose of study drug; 4) Requirement for systemic corticosteroids (greater than 10 mg/day prednisone equivalent) or other immunosuppressive agents within 2 weeks before the first dose of study drug; exceptions include the use of corticosteroids for local inflammation and for prophylaxis of allergy, nausea and vomiting; 5) Major surgery or severe trauma within 4 weeks before the first dose of study drug, or elective surgery planned during the study period; a traumatic minor procedure (e.g., needle biopsy) within 7 days before the first dose.
• History of hypersensitivity to monoclonal antibodies or to any of the formulation excipients of trastuzumab rezetecan.
• Toxicities from prior anticancer therapy that have not recovered to CTCAE v5.0 grade ≤ 1 (except toxicities judged by the investigator to carry no safety risk, e.g., alopecia) or to the level specified in the inclusion/exclusion criteria; participants who have received immune checkpoint inhibitors and have type 1 diabetes mellitus or hypothyroidism that is stable on hormone replacement therapy are eligible.
• History of or current leptomeningeal metastasis; presence of active brain metastasis, defined as untreated and/or symptomatic disease, or disease requiring corticosteroids or antiepileptic drugs to control related symptoms. Participants who have received surgery or radiotherapy are eligible if screening imaging shows no evidence of progression for at least 4 weeks and symptoms have resolved (except residual signs or symptoms related to CNS treatment), corticosteroids have not been required for at least 2 weeks, and acute toxicities related to prior therapy have recovered.
• Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage.
• Within 28 days before the first dose of study drug: inability to swallow, chronic diarrhea, gastroenteritis, intestinal obstruction, gastrointestinal perforation, ulcerative colitis or inflammatory bowel disease, or any other disease or condition that may affect oral administration or absorption of the study drug.
• Bleeding tendency, high bleeding risk, coagulation disorder or thrombotic tendency, including but not limited to: imaging evidence that the tumor has invaded a major vessel, or, in the investigator's judgment, a high likelihood that the tumor will invade a major vessel during the study and cause fatal massive bleeding; grade > 1 pulmonary hemorrhage or grade > 2 bleeding at other sites within 4 weeks before enrollment; bleeding tendency (e.g., active peptic ulcer), or current treatment with thrombolytic or anticoagulant agents such as warfarin, heparin or their analogues.
• Presence of a non-healing wound (severe, non-healing or dehisced), active peptic ulcer, or untreated fracture.
• History of immunodeficiency, including a positive HIV test, or other acquired or congenital immunodeficiency disease, or a history of organ transplantation or allogeneic bone marrow transplantation.
• Unexplained fever greater than 38.5 °C during screening or before the first dose (participants with tumor-related fever, as judged by the investigator, may be enrolled); severe infection (CTCAE grade > 2) within 4 weeks before the first dose of study drug, e.g., severe pneumonia, bacteremia or infectious complications requiring hospitalization; baseline chest imaging showing active pulmonary inflammation, or signs and symptoms of infection requiring oral or intravenous antibiotic therapy within 2 weeks before the first dose of study drug, except for prophylactic antibiotic use.
• Known or suspected interstitial pneumonitis; other severe pulmonary disease significantly impairing respiratory function within 3 months before the first dose, including but not limited to idiopathic pulmonary fibrosis, organizing pneumonia/bronchiolitis obliterans, severe COPD, and severe obstructive or restrictive ventilatory dysfunction. Participants who developed grade ≥ 3 interstitial or immune-mediated pneumonitis during prior immune checkpoint inhibitor therapy, or who permanently discontinued such therapy because of interstitial or immune-mediated pneumonitis, are not eligible for this study.
• Active hepatitis B (HBV DNA ≥ 500 IU/mL); hepatitis C (HCV antibody positive with HCV-RNA above the lower limit of detection of the assay).
• Clinically significant cardiovascular disease, such as severe/unstable angina pectoris, symptomatic congestive heart failure (NYHA ≥ class II), clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention, arterial or venous thrombosis within 6 months before the first dose (except thromboses judged by the investigator to be not clinically significant, e.g., transient thrombosis caused by PICC line placement), acute coronary syndrome, myocardial infarction, cerebrovascular accident (including transient ischemic attack), or other grade ≥ 3 cardiovascular or cerebrovascular events; QTcF greater than 450 ms (male) or greater than 470 ms (female) on 12-lead ECG at rest; left ventricular ejection fraction < 50%; clinically uncontrolled hypertension.
• Other malignancy within the past 5 years, except cured basal cell carcinoma of the skin and carcinoma in situ of the cervix.
• Pregnant or breastfeeding women.
• Any other factor that, in the investigator's judgment, may result in the participant's forced early termination from the study, such as other serious disease (including psychiatric disease) requiring concomitant treatment, severe laboratory abnormalities, or family or social factors that may affect the participant's safety or the collection of study data.