AK104 Plus Radiotherapy Combined With Standard Therapy Versus Standard Therapy as First-Line Treatment for pMMR/MSS CRLM (APSOC)

Efficacy of Cadonilimab (AK104) Plus Radiotherapy Combined With Standard Therapy Versus Standard Therapy as First-Line Treatment for pMMR/MSS Colorectal Cancer With Liver Metastases: A Prospective, Randomized Controlled, Single-Center Phase II Clinical Trial (APSOC)

This is a prospective, randomized controlled, single-center phase II clinical study. It aims to compare the efficacy of AK104 plus radiotherapy combined with standard therapy versus standard therapy as first-line treatment for liver metastases from metastatic colorectal cancer.

Inclusion Criteria:

1. Age ≥ 18 years, with no gender restriction;

2. Histologically or cytologically confirmed colorectal cancer;

3. Presence of liver metastases, with at least one measurable target lesion (per RECIST 1.1 criteria) in addition to a single liver metastatic lesion amenable to radiotherapy; patients with initially resectable colorectal cancer liver metastases are excluded;

4. Treatment-naive patients; or patients with postoperative recurrence who have not received any anti-tumor therapy within 6 months and at least 6 months have elapsed since the last adjuvant chemotherapy;

5. ECOG performance status score of 0-1;

6. Expected overall survival ≥ 3 months;

7. Adequate organ function and reserve, meeting the following laboratory criteria within 7 days prior to screening (inclusive):

   HB ≥ 90 g/dL, ANC ≥ 1.5 × 10⁹/L, PLT ≥ 100 × 10⁹/L; BIL < 1.5 × ULN, ALT and AST < 2.5 × ULN; ALT and AST < 5 × ULN in the presence of liver metastases; Serum Cr ≤ 1 × ULN, creatinine clearance > 50 mL/min (calculated using the Cockcroft-Gault formula); International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN; for patients on anticoagulant therapy, PT within the intended therapeutic range is acceptable;

8. Voluntary participation in the study, provision of signed informed consent, good compliance, and willingness to comply with follow-up procedures.

Exclusion Criteria:

1. History of other malignancy within 3 years prior to enrollment, except for cured carcinoma in situ of the cervix or basal cell carcinoma of the skin.

2. Symptomatic brain or meningeal metastases, except those treated locally and stable for more than 2 months without symptoms.

3. Presence of gastrointestinal obstruction, gastrointestinal bleeding (≥+++ fecal occult blood), or perforation.

4. Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, CD137, or CTLA-4 antibodies, or any other antibodies or drugs specifically targeting T-cell co-stimulatory or checkpoint pathways.

5. Subjects with active autoimmune disease or a history of autoimmune disease that may relapse (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid disease, multiple sclerosis, vasculitis, glomerulonephritis, etc.), or patients at high risk (e.g., organ transplant recipients requiring immunosuppressive therapy).

   However, patients with vitiligo, psoriasis, alopecia, or Graves' disease not requiring systemic therapy in the past 2 years, hypothyroidism requiring only thyroid hormone replacement, or type 1 diabetes mellitus requiring only insulin replacement may be enrolled.

6. Current interstitial lung disease or pneumonitis, pulmonary fibrosis, acute pulmonary disease, or radiation pneumonitis.

7. Participation in another investigational drug study within 4 weeks prior to the first dose (based on receipt of investigational product), unless participation was in an observational (non-interventional) study.

8. Use of immunosuppressive medications within 4 weeks prior to the first study treatment, excluding topical, nasal, inhaled, or other local corticosteroids; physiological doses of systemic corticosteroids (i.e., ≤10 mg/day prednisone or equivalent); or short-term (≤7 days) corticosteroids for prophylaxis or treatment of non-autoimmune allergic conditions.

9. Administration of a live attenuated vaccine within 4 weeks prior to the first dose or planned administration during the study period.

   Note: Administration of inactivated seasonal influenza vaccine by injection within 4 weeks prior to the first dose is permitted; live attenuated influenza vaccines are not permitted.

10. Major surgical procedure (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the first study treatment, or expectation of requiring major non-study surgery during the study period.

11. History of human immunodeficiency virus (HIV) infection (i.e., positive HIV antibody), other acquired or congenital immunodeficiency disorders, organ transplantation, or stem cell transplantation.

12. Active chronic hepatitis B or active hepatitis C. Hepatitis B carriers, patients with hepatitis B stabilized by antiviral therapy (HBV DNA ≤ 200 IU/mL or copy number < 1000 copies/mL), and patients with cured hepatitis C (negative HCV RNA) may be enrolled.

13. Known active tuberculosis.

14. Severe infection within 4 weeks prior to the first dose, or active infection requiring oral or intravenous antibiotic therapy within 2 weeks prior to the first dose.

15. Symptomatic congestive heart failure (NYHA Class II-IV) or symptomatic or poorly controlled cardiac arrhythmia.

16. Uncontrolled arterial hypertension despite standard treatment (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg).

17. Any arterial thromboembolic event within 6 months prior to enrollment, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack.

18. History of deep vein thrombosis, pulmonary embolism, or other severe thromboembolism within 3 months prior to enrollment.

    Catheter-related thrombosis or superficial venous thrombosis associated with an implanted venous port or catheter is not considered severe thromboembolism.

19. Documented history of neurological or psychiatric disorders: e.g., epilepsy, dementia, poor compliance, or presence of peripheral neurological disorders.

20. Alcohol dependence or history of drug abuse within the past 1 year.

21. Pregnant or lactating women; individuals of childbearing potential without adequate contraception.

22. Other acute or chronic medical conditions, psychiatric disorders, or abnormal laboratory values that may: increase the risk associated with study participation or study drug administration; interfere with the interpretation of study results; and in the opinion of the investigator, render the patient ineligible for study participation.