QL1706 Plus Bevacizumab for Unresectable or Metastatic MSI-H/dMMR CRC

• Voluntarily signs the informed consent form.
• Aged between 18 and 80 years (inclusive) at the time of consent; no gender restriction.
• Histologically confirmed unresectable locally advanced or metastatic colorectal cancer.
• At least one measurable target lesion according to RECIST v1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• No prior immunotherapy for unresectable locally advanced or metastatic colorectal cancer.
• If previously treated with standard neoadjuvant or adjuvant therapy, the interval from the last dose to the first study treatment must be ≥ 6 months.
• Willing and able to provide tumor tissue and blood samples for MSI, RAS, BRAF, and PD-L1 testing.
• Estimated life expectancy of ≥ 12 months.
• Appropriate laboratory values must be met at screening.
• Female participants must be non-lactating, and have a negative pregnancy test result prior to enrollment.
• Participants of childbearing potential must agree to use effective contraception from the time of informed consent until at least 180 days after the last dose of study treatment.

Exclusion Criteria:

• Known history of severe allergic reactions to iparomlimab and tuvonralimab or bevacizumab.
• Active malignancy other than colorectal cancer within 5 years prior to first treatment.
• Large tumor lesions, especially those previously irradiated, with signs of bleeding.
• Imaging showing tumor invasion of major blood vessels (e.g., pulmonary artery or superior vena cava), including encasement or invasion of the vessel lumen.
• Brain metastases (asymptomatic or treated symptomatic brain metastases stable for >4 weeks allowed).
• Active autoimmune disease requiring systemic treatment.
• Active pulmonary diseases such as tuberculosis, radiation pneumonitis, drug-induced pneumonitis, or severe pulmonary dysfunction during screening.
• Requirement for long-term or high-dose NSAIDs (aspirin >325 mg) or anticoagulant therapy.
• History of severe gastrointestinal events within 6 months prior to first treatment.
• Severe intestinal obstruction symptoms or signs and unretrieved intestinal stents at screening.
• Cardiovascular or cerebrovascular diseases including but not limited to: NYHA class > II heart failure; unstable or severe angina; myocardial infarction or stroke within 6 months; atrial fibrillation or other arrhythmias requiring treatment; symptomatic superior vena cava syndrome; prolonged QT interval (male QT > 450 ms; female QTc > 470 ms); uncontrolled hypertension despite medication (SBP >140 mmHg and/or DBP >90 mmHg) or history of hypertensive crisis or encephalopathy.
• Known bleeding disorders or coagulopathies.
• Uncontrolled pleural, pericardial, or ascitic effusions requiring drainage.
• Active infection or unexplained fever >38.5°C at screening (cancer-related fever allowed).
• Use of systemic broad-spectrum antibiotics within 30 days prior to first treatment.
• Systemic corticosteroids (>10 mg prednisone equivalent daily) or immunosuppressants within 14 days prior to first treatment, or immunostimulants within 4 weeks.
• Major surgery, severe fractures, or therapeutic clinical trials within 4 weeks prior to first treatment; herbal treatment within 2 weeks.
• Ongoing adverse events from prior antitumor therapy greater than grade 1.
• HIV infection, other congenital or acquired immunodeficiencies, or history of organ or allogeneic bone marrow transplantation (except corneal transplantation).
• Positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HBcAb) with HBV DNA >10⁴ copies/mL (\~2000 IU/mL); or positive hepatitis C antibody with HCV RNA >10³ copies/mL; co-infection with HBV and HCV excluded.
• Vaccination with live or attenuated vaccines within 30 days prior to first treatment.
• Prior treatment with immune checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-OX-40, anti-CD137).
• Prior adjuvant targeted therapy against EGFR, VEGF, or VEGFR (e.g., bevacizumab, cetuximab, panitumumab, apatinib, regorafenib, anlotinib).
• Psychiatric disorders, epilepsy, dementia, or substance abuse that may affect compliance.
• Other conditions or lab abnormalities that may interfere with study participation or confound results as judged by investigators or sponsors.