This is a Phase III, randomized, open-label, active-controlled, multicenter study designed to evaluate the efficacy and safety of Injection TQB2102 compared with investigator's choice of treatment in subjects with Human Epidermal Growth Factor Receptor 2 (HER2) ImmunoHistoChemistry score 3 (IHC3+) advanced colorectal cancer who have failed prior treatment with oxaliplatin, irinotecan, and fluoropyrimidine-based regimens.

The primary endpoint of this study is progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). The key secondary endpoint is overall survival (OS). Other secondary endpoints include investigator-assessed PFS, objective response rate (ORR), duration of response (DOR), disease control rate (DCR), time to response (TTR), safety, and quality of life scores.

Approximately 142 subjects are planned to be enrolled. Eligible subjects will be randomly assigned in a 1:1 ratio to the experimental group or the control group.

Inclusion Criteria:

• The subject voluntarily participates in this study, signs the informed consent form, and has good compliance.
• Aged 18 to 75 years old (calculated as of the date of signing the informed consent form).
• Subjects with histologically or cytologically confirmed advanced colorectal cancer.
• The subject has confirmed HER2 IHC3+ status in tumor tissue, as determined by the central laboratory designated by the sponsor.
• The subject must provide a sufficient quantity of qualified tumor specimens (fresh or archived samples collected within the past 3 years from primary or metastatic lesions) for central laboratory testing of HER2 status.
• Advanced colorectal cancer that has progressed on or been intolerant to at least 2 prior lines of standard therapy (defined as disease progression or intolerable toxicity during or within 3 months after the last standard therapy).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Expected survival of greater than 12 weeks.
• Presence of at least one measurable lesion as confirmed by RECIST 1.1 criteria.
• Laboratory tests must meet criteria
• Women of childbearing potential must agree to use effective contraception during the study and for 6 months after the study ends, and have a negative serum or urine pregnancy test within 7 days prior to study entry. Men must agree to use effective contraception during the study and for 6 months after the study ends.

Exclusion Criteria:

• A history of other malignant tumors within 3 years prior to the first dose, or concurrent malignant tumors at screening. Subjects are eligible for enrollment if they meet one of the following two conditions:

  • Other malignant tumors treated with curative intent via a single surgical procedure, with disease-free survival (DFS) maintained for 5 consecutive years;
  • A history of cured carcinoma in situ of the cervix, non-melanoma skin cancer, or superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor invading the basement membrane)].

• Presence of diseases that affect intravenous injection or venous blood collection, or factors that impair oral drug administration (e.g., dysphagia, chronic diarrhea, intestinal obstruction, etc.).

• Failure of adverse reactions from prior treatments to resolve to ≤ Grade 1 per CTCAE v5.0, with the following exceptions: Grade 2 alopecia, Grade 2 peripheral neurotoxicity, Grade 2 anemia, non-clinically significant and asymptomatic laboratory abnormalities, type 1 diabetes mellitus and hypothyroidism stabilized with hormone replacement therapy, and other toxicities judged by the investigator to pose no safety risks.

• Receipt of major surgical treatment, significant traumatic injury within 4 weeks prior to the first dose; or planned major surgery during the study period (excluding surgeries specified in the protocol); or presence of unhealed wounds or fractures for a prolonged period.

• Clinically significant tumor bleeding or perforation within 1 month prior to the first dose; or any bleeding event ≥ Grade 3 per CTCAE v5.0; or subjects with bleeding or coagulation disorders receiving warfarin, aspirin, or other antiplatelet agents (excluding maintenance doses: aspirin ≤ 100 mg/day, clopidogrel ≤ 75 mg/day); or subjects with a history or signs of bleeding deemed ineligible by the investigator.

• A history of thrombotic or embolic events within 6 months prior to the first dose, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis (DVT) [excluding subjects with isolated calf vein thrombosis ≤ 7 mm in diameter, ≤ 5 cm in length, not involving ≥ 2 veins, and assessed by the investigator as having no risk of thrombus progression], and pulmonary embolism, etc.

• Presence of major cardiovascular diseases.

• A history of decompensated liver cirrhosis or hepatic encephalopathy.

• Subjects with active chronic hepatitis B or active chronic hepatitis C. Subjects positive for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody at screening must undergo additional testing for Hepatitis B Virus (HBV) DNA titer or HCV RNA quantification.

• Active syphilis infection requiring treatment.

• A history of (non-infectious) pneumonitis/interstitial lung disease requiring corticosteroid therapy; or current diagnosis of non-infectious pneumonitis/interstitial lung disease; or hospitalization for any active infection or receipt of therapeutic antibiotics within 4 weeks prior to the start of study treatment, including but not limited to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

• Active or uncontrolled severe infection (≥ Grade 2 infection per CTCAE v5.0).

• A history of psychoactive substance abuse with inability to abstain, or presence of mental disorders.

• A history of immunodeficiency, including HIV positivity, other acquired or congenital immunodeficiency diseases, or a history of organ transplantation.

• Tumor-related symptoms and treatments.

• Known hypersensitivity or allergic reaction to any study drug or its excipients.

• Prior receipt of anti-HER2 antibody-drug conjugate (ADC) therapy.

• Receipt of any anticancer therapy (including chemotherapy, targeted therapy, immunotherapy, etc.) or any other investigational drug therapy within 4 weeks or 5 half-lives prior to the first dose of this study, whichever is shorter.

• Pregnant or lactating subjects.

• Vaccination with live-attenuated vaccines within 28 days prior to the start of study treatment, or inactivated vaccines within 7 days prior; or planned vaccination during the study period.

• Any other condition judged by the investigator to pose a serious risk to subject safety or interfere with the subject's completion of the study.